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  • 1.
    Bourghardt, Johan
    et al.
    Wallenberg Laboratory for Cardiovascular Research, Göteborg University, Sahlgrenska University Hospital, Göteborg, Sweden.
    Bergström, Göran
    Wallenberg Laboratory for Cardiovascular Research, Göteborg University, Sahlgrenska University Hospital, Göteborg, Sweden.
    Krettek, Alexandra
    Wallenberg Laboratory for Cardiovascular Research, Göteborg University, Sahlgrenska University Hospital, Göteborg, Sweden.
    Sjöberg, Sara
    Wallenberg Laboratory for Cardiovascular Research, Göteborg University, Sahlgrenska University Hospital, Göteborg, Sweden.
    Borén, Jan
    Wallenberg Laboratory for Cardiovascular Research, Göteborg University, Sahlgrenska University Hospital, Göteborg, Sweden.
    Tivesten, Åsa
    Wallenberg Laboratory for Cardiovascular Research, Göteborg University, Sahlgrenska University Hospital, Göteborg, Sweden / Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital, Göteborg, Sweden.
    The endogenous estradiol metabolite 2-methoxyestradiol reduces atherosclerotic lesion formation in female apolipoprotein E-deficient mice2007In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 148, no 9, p. 4128-4132Article in journal (Refereed)
    Abstract [en]

    Estradiol, the major endogenous estrogen, reduces experimental atherosclerosis and metabolizes to 2-methoxyestradiol in vascular cells. Currently undergoing evaluation in clinical cancer trials, 2-methoxyestradiol potently inhibits cell proliferation independently of the classical estrogen receptors. This study examined whether 2-methoxyestradiol affects atherosclerosis development in female mice. Apolipoprotein E-deficient mice, a well-established mouse model of atherosclerosis, were ovariectomized and treated through slow-release pellets with placebo, 17beta-estradiol (6 microg/d), or 2-methoxyestradiol [6.66 microg/d (low-dose) or 66.6 microg/d (high-dose)]. After 90 d, body weight gain decreased and uterine weight increased in the high-dose but not low-dose 2-methoxyestradiol group. En face analysis showed that the fractional area of the aorta covered by atherosclerotic lesions decreased in the high-dose 2-methoxyestradiol (52%) but not in the low-dose 2-methoxyestradiol group. Total serum cholesterol levels decreased in the high- and low-dose 2-methoxyestradiol groups (19%, P < 0.05 and 21%, P = 0.062, respectively). Estradiol treatment reduced the fractional atherosclerotic lesion area (85%) and decreased cholesterol levels (42%). In conclusion, our study shows for the first time that 2-methoxyestradiol reduces atherosclerotic lesion formation in vivo. The antiatherogenic activity of an estradiol metabolite lacking estrogen receptor activating capacity may argue that trials on cardiovascular effects of hormone replacement therapy should use estradiol rather than other estrogens. Future research should define the role of 2-methoxyestradiol as a mediator of the antiatherosclerotic actions of estradiol. Furthermore, evaluation of the effects of 2-methoxyestradiol on cardiovascular disease endpoints in ongoing clinical trials is of great interest.

  • 2.
    Bourghardt, Johan
    et al.
    Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, Sweden.
    Wilhelmson, Anna S. K.
    Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, Sweden.
    Alexanderson, Camilla
    Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, Sweden.
    De Gendt, Karel
    Laboratory for Experimental Medicine and Endocrinology, Department of Experimental Medicine, Katholieke Universiteit Leuven, Leuven, Belgium.
    Verhoeven, Guido
    Laboratory for Experimental Medicine and Endocrinology, Department of Experimental Medicine, Katholieke Universiteit Leuven, Leuven, Belgium.
    Krettek, Alexandra
    Nordic School of Public Health NHV, Gothenburg, Sweden.
    Ohlsson, Claes
    Center for Bone Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Tivesten, Åsa
    Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, Sweden.
    Androgen receptor-dependent and independent atheroprotection by testosterone in male mice2010In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 151, no 11, p. 5428-5437Article in journal (Refereed)
    Abstract [en]

    The atheroprotective effect of testosterone is thought to require aromatization of testosterone to estradiol, but no study has adequately addressed the role of the androgen receptor (AR), the major pathway for the physiological effects of testosterone. We used AR knockout (ARKO) mice on apolipoprotein E-deficient background to study the role of the AR in testosterone atheroprotection in male mice. Because ARKO mice are testosterone deficient, we sham operated or orchiectomized (Orx) the mice before puberty, and Orx mice were supplemented with placebo or a physiological testosterone dose. From 8 to 16 wk of age, the mice consumed a high-fat diet. In the aortic root, ARKO mice showed increased atherosclerotic lesion area (+80%, P < 0.05). Compared with placebo, testosterone reduced lesion area both in Orx wild-type (WT) mice (by 50%, P < 0.001) and ARKO mice (by 24%, P < 0.05). However, lesion area was larger in testosterone-supplemented ARKO compared with testosterone-supplemented WT mice (+57%, P < 0.05). In WT mice, testosterone reduced the presence of a necrotic core in the plaque (80% among placebo-treated vs. 12% among testosterone-treated mice; P < 0.05), whereas there was no significant effect in ARKO mice (P = 0.20). In conclusion, ARKO mice on apolipoprotein E-deficient background display accelerated atherosclerosis. Testosterone treatment reduced atherosclerosis in both WT and ARKO mice. However, the effect on lesion area and complexity was more pronounced in WT than in ARKO mice, and lesion area was larger in ARKO mice even after testosterone supplementation. These results are consistent with an AR-dependent as well as an AR-independent component of testosterone atheroprotection in male mice.

  • 3.
    Dollery, Clare M.
    et al.
    Leducq Ctr. for Cardiovasc. Research, Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States.
    Owen, Caroline A.
    Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States.
    Sukhova, Galina K
    Leducq Ctr. for Cardiovasc. Research, Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States.
    Krettek, Alexandra
    Leducq Ctr. for Cardiovasc. Research, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.
    Shapiro, Steven D.
    Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States.
    Libby, Peter
    Leducq Ctr. for Cardiovasc. Research, Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States / Brigham and Women's Hospital, Harvard Medical School, EBRC 307, 221 Longwood Ave., Boston, MA 02115, United States.
    Neutrophil elastase in human atherosclerotic plaques: production by macrophages2003In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 107, no 22, p. 2829-2836Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Catabolism of the extracellular matrix (ECM) contributes to vascular remodeling in health and disease. Although metalloenzymes and cysteinyl proteinases have garnered much attention in this regard, the role of serine-dependent proteinases in vascular ECM degradation during atherogenesis remains unknown. We recently discovered the presence of the metalloproteinase MMP-8, traditionally associated only with neutrophils, in atheroma-related cells. Human neutrophil elastase (NE) plays a critical role in lung disease, but the paucity of neutrophils in the atheromatous plaque has led to neglect of its potential role in vascular biology. NE can digest elastin, fibrillar and nonfibrillar collagens, and other ECM components in addition to its ability to modify lipoproteins and modulate cytokine and MMP activity.

    METHODS AND RESULTS: Fibrous and atheromatous plaques but not normal arteries contained NE. In particular, NE abounded in the macrophage-rich shoulders of atheromatous plaques with histological features of vulnerability. Neutrophil elastase and macrophages colocalized in such vulnerable plaques (n=7). In situ hybridization revealed NE mRNA in macrophage-rich areas, indicating local production of this enzyme. Freshly isolated blood monocytes, monocyte-derived macrophages, and vascular endothelial cells in culture produced active NE and contained NE mRNA. Monocytes produced NE constitutively, with little regulation by cytokines IL-1beta, TNF-alpha, or IFN-gamma but released it when stimulated by CD40 ligand, a cytokine found in atheroma.

    CONCLUSIONS: These findings point to a novel role for the serine protease, neutrophil elastase, in matrix breakdown by macrophages, a critical process in adaptive remodeling of vessels and in the pathogenesis of arterial diseases.

  • 4.
    Fagman, Johan B.
    et al.
    Wallenberg Laboratory for Cardiovascular and Metabolic Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Wilhelmson, Anna S.
    Wallenberg Laboratory for Cardiovascular and Metabolic Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Motta, Benedetta M.
    Wallenberg Laboratory for Cardiovascular and Metabolic Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Pirazzi, Carlo
    Wallenberg Laboratory for Cardiovascular and Metabolic Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Alexanderson, Camilla
    Wallenberg Laboratory for Cardiovascular and Metabolic Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    De Gendt, Karel
    Laboratory for Experimental Medicine and Endocrinology, Department of Experimental Medicine, Katholieke Universiteit Leuven, Leuven, Belgium.
    Verhoeven, Guido
    Laboratory for Experimental Medicine and Endocrinology, Department of Experimental Medicine, Katholieke Universiteit Leuven, Leuven, Belgium.
    Holmäng, Agneta
    Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Anesten, Fredrik
    Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Jansson, John-Olov
    Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Levin, Malin
    Wallenberg Laboratory for Cardiovascular and Metabolic Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Borén, Jan
    Wallenberg Laboratory for Cardiovascular and Metabolic Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Ohlsson, Claes
    Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Krettek, Alexandra
    Nordic School of Public Health, Gothenburg, Sweden / Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Romeo, Stefano
    Wallenberg Laboratory for Cardiovascular and Metabolic Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Tivesten, Åsa
    Wallenberg Laboratory for Cardiovascular and Metabolic Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    The androgen receptor confers protection against diet-induced atherosclerosis, obesity, and dyslipidemia in female mice2015In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 29, no 4, p. 1540-1550Article in journal (Refereed)
    Abstract [en]

    Androgens have important cardiometabolic actions in males, but their metabolic role in females is unclear. To determine the physiologic androgen receptor (AR)-dependent actions of androgens on atherogenesis in female mice, we generated female AR-knockout (ARKO) mice on an atherosclerosis-prone apolipoprotein E (apoE)-deficient background. After 8 weeks on a high-fat diet, but not on a normal chow diet, atherosclerosis in aorta was increased in ARKO females (+59% vs. control apoE-deficient mice with intact AR gene). They also displayed increased body weight (+18%), body fat percentage (+62%), and hepatic triglyceride levels, reduced insulin sensitivity, and a marked atherogenic dyslipidemia (serum cholesterol, +52%). Differences in atherosclerosis, body weight, and lipid levels between ARKO and control mice were abolished in mice that were ovariectomized before puberty, consistent with a protective action of ovarian androgens mediated via the AR. Furthermore, the AR agonist dihydrotestosterone reduced atherosclerosis (-41%; thoracic aorta), subcutaneous fat mass (-44%), and cholesterol levels (-35%) in ovariectomized mice, reduced hepatocyte lipid accumulation in hepatoma cells in vitro, and regulated mRNA expression of hepatic genes pivotal for lipid homeostasis. In conclusion, we demonstrate that the AR protects against diet-induced atherosclerosis in female mice and propose that this is mediated by modulation of body composition and lipid metabolism.-Fagman, J. B., Wilhelmson, A. S., Motta, B. M., Pirazzi, C., Alexanderson, C., De Gendt, K., Verhoeven, G., Holmäng, A., Anesten, F., Jansson, J. -O., Levin, M., Borén, J., Ohlsson, C., Krettek, A., Romeo, S., Tivesten, A. The androgen receptor confers protection against diet-induced atherosclerosis, obesity, and dyslipidemia in female mice.

  • 5.
    Hultén, Lillemor Mattsson
    et al.
    Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital, Göteborg, Sweden.
    Ullström, Christina
    Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital, Göteborg, Sweden.
    Krettek, Alexandra
    Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital, Göteborg, Sweden.
    van Reyk, David
    Department of Health Sciences, University of Technology, Sydney, Australia.
    Marklund, Stefan L.
    Medical Biosciences, Clinical Chemistry, Umeå University Hospital, Umeå, Sweden.
    Dahlgren, Claes
    Phagocyte Research Laboratory, Department of Rheumatology and Inflammation Research, University of Göteborg, Göteborg, Sweden.
    Wiklund, Olov
    Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital, Göteborg, Sweden.
    Human macrophages limit oxidation products in low density lipoprotein2005In: Lipids in Health and Disease, ISSN 1476-511X, E-ISSN 1476-511X, Vol. 4, article id 6Article in journal (Refereed)
    Abstract [en]

    This study tested the hypothesis that human macrophages have the ability to modify oxidation products in LDL and oxidized LDL (oxLDL) via a cellular antioxidant defence system. While many studies have focused on macrophage LDL oxidation in atherosclerosis development, less attention has been given to the cellular antioxidant capacity of these cells. Compared to cell-free controls (6.2 +/- 0.7 nmol/mg LDL), macrophages reduced TBARS to 4.42 +/- 0.4 nmol/mg LDL after 24 h incubation with LDL (P = 0.022). After 2 h incubation with oxLDL, TBARS were 3.69 +/- 0.5 nmol/mg LDL in cell-free media, and 2.48 +/- 0.9 nmol/mg LDL in the presence of macrophages (P = 0.034). A reduction of lipid peroxides in LDL (33.7 +/- 6.6 nmol/mg LDL) was found in the presence of cells after 24 h compared to cell-free incubation (105.0 +/- 14.1 nmol/mg LDL) (P = 0.005). The levels of lipid peroxides in oxLDL were 137.9 +/- 59.9 nmol/mg LDL and in cell-free media 242 +/- 60.0 nmol/mg LDL (P = 0.012). Similar results were obtained for hydrogen peroxide. Reactive oxygen species were detected in LDL, acetylated LDL, and oxLDL by isoluminol-enhanced chemiluminescence (CL). Interestingly, oxLDL alone gives a high CL signal. Macrophages reduced the CL response in oxLDL by 45% (P = 0.0016). The increased levels of glutathione in oxLDL-treated macrophages were accompanied by enhanced catalase and glutathione peroxidase activities. Our results suggest that macrophages respond to oxidative stress by endogenous antioxidant activity, which is sufficient to decrease reactive oxygen species both in LDL and oxLDL. This may suggest that the antioxidant activity is insufficient during atherosclerosis development. Thus, macrophages may play a dual role in atherogenesis, i.e. both by promoting and limiting LDL-oxidation.

  • 6.
    Hägg, Daniel
    et al.
    Research Center for Endocrinology and Metabolism, Department of Metabolism and Cardiovascular Research, Göteborg, Sweden.
    Sjöberg, Sara
    Research Center for Endocrinology and Metabolism, Department of Metabolism and Cardiovascular Research, Göteborg, Sweden.
    Hultén, Lillemor Mattsson
    Wallenberg Laboratory for Cardiovascular Research, Department of Metabolism and Cardiovascular Research, Göteborg, Sweden.
    Fagerberg, Björn
    Wallenberg Laboratory for Cardiovascular Research, Department of Metabolism and Cardiovascular Research, Göteborg, Sweden.
    Wiklund, Olov
    Wallenberg Laboratory for Cardiovascular Research, Department of Metabolism and Cardiovascular Research, Göteborg, Sweden.
    Rosengren, Annika
    Department of Acute and Cardiovascular Medicine, Sahlgrenska Academy, Göteborg University, Göteborg, Sweden.
    Carlsson, Lena M. S.
    Research Center for Endocrinology and Metabolism, Department of Metabolism and Cardiovascular Research, Göteborg, Sweden.
    Borén, Jan
    Wallenberg Laboratory for Cardiovascular Research, Department of Metabolism and Cardiovascular Research, Göteborg, Sweden.
    Svensson, Per-Arne
    Research Center for Endocrinology and Metabolism, Department of Metabolism and Cardiovascular Research, Göteborg, Sweden / Wallenberg Laboratory for Cardiovascular Research, Department of Metabolism and Cardiovascular Research, Göteborg, Sweden.
    Krettek, Alexandra
    Wallenberg Laboratory for Cardiovascular Research, Department of Metabolism and Cardiovascular Research, Göteborg, Sweden.
    Augmented levels of CD44 in macrophages from atherosclerotic subjects: a possible IL-6-CD44 feedback loop?2007In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 190, no 2, p. 291-297Article in journal (Refereed)
    Abstract [en]

    The cell-adhesion molecule CD44 likely participates in atherosclerosis development. We have shown previously that pro-inflammatory cytokines affect CD44 expression. Therefore, this work examined the role of elevated CD44 levels in human macrophages. Macrophages from human atherosclerotic subjects (n=15) showed elevated levels of CD44 transcript and protein (1.5-fold) compared to matched controls (n=15) (P=0.050 and 0.044, respectively). To test whether genetic factors influence CD44 expression, two single nucleotide polymorphisms in the CD44 gene were analyzed but these were not associated with coronary artery disease. We also examined the potential connection between plasma cytokine levels and CD44 expression. In atherosclerotic subjects, elevated CD44 expression correlates (P=0.012) with enhanced macrophage IL-6 secretion (3.13+/-2.5 pg/mL versus 0.32+/-0.16 pg/mL in controls, P=0.021). Additionally, CD44-deficient mice exhibit less circulating IL-6 than wild-type controls (9.8+/-0.7 pg/mL versus 14.3+/-0.7 pg/mL; P=0.032). Furthermore, IL-6 augments CD44 expression in primary human macrophages after 24 h (P=0.038) and 48 h (P=0.015). Taken together, our data show an IL-6-CD44 feedback loop in macrophages. Such a positive feedback loop may aggravate atherosclerosis development.

  • 7.
    Krettek, Alexandra
    et al.
    The Wallenberg Laboratory for Cardiovascular Research, Göteborg University, Sahlgrenska University Hospital, Göteborg, Sweden.
    Fager, G.
    The Wallenberg Laboratory for Cardiovascular Research, Göteborg University, Sweden.
    Jernberg, P.
    The Wallenberg Laboratory for Cardiovascular Research, Göteborg University, Sweden.
    Östergren-Lundén, G.
    The Wallenberg Laboratory for Cardiovascular Research, Göteborg University, Sweden.
    Lustig, F.
    The Wallenberg Laboratory for Cardiovascular Research, Göteborg University, Sweden.
    Quantitation of platelet-derived growth factor receptors in human arterial smooth muscle cells in vitro1997In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 17, no 11, p. 2395-2404Article in journal (Refereed)
    Abstract [en]

    Platelet-derived growth factor (PDGF) is suggested to play an important role in the development of atherosclerosis as a migratory and mitogenic stimulus to arterial smooth muscle cells (ASMCs). Stimulated and unstimulated ASMCs were studied with respect to PDGF receptor (PDGF-R) mRNA and protein expression. Quantitative RT-PCR was developed for simultaneous evaluation of both PDGF-R alpha and -R beta mRNA expression and a quantitative ELISA for estimation of corresponding PDGF-R subunits. On the mRNA level, the overall PDGF-R beta expression was approximately 100 times lower than that of PDGF-R alpha. Furthermore, although PDGF-R alpha mRNA levels were high irrespective of hASMC phenotype, PDGF-R beta mRNA was influenced by serum stimulation with lower copy numbers in proliferating and confluent cells compared with quiescent cells. On the protein level, quiescent hASMCs expressed 10 times more PDGF-R beta than PDGF-R alpha. Serum stimulation decreased cell surface PDGF-Rs, with most prominent loss of PDGF-R alpha (ELISA and immunohistochemistry). Our results suggest a differential regulatory pattern for PDGF-R alpha and -R beta and are compatible with the usage of alternative promoters for regulation of -R alpha expression. Further, it seems that the number of available receptor subunits is not the only determinant of variations in cell stimulation with different PDGF isoforms.

  • 8.
    Krettek, Alexandra
    et al.
    Wellenberg Lab. for Cardiovasc. Res., Göteborg University, Sahlgrenska University Hospital, Göteborg, Sweden / Wallenberg Lab. for Cardiovasc. Res., Göteborg University, Sahlgrenska University Hospital, Göteborg, Sweden.
    Fager, G.
    Wellenberg Lab. for Cardiovasc. Res., Göteborg University, Sahlgrenska University Hospital, Göteborg, Sweden.
    Lindmark, H.
    Wellenberg Lab. for Cardiovasc. Res., Göteborg University, Sahlgrenska University Hospital, Göteborg, Sweden.
    Simonson, C.
    Wellenberg Lab. for Cardiovasc. Res., Göteborg University, Sahlgrenska University Hospital, Göteborg, Sweden.
    Lustig, F.
    Wellenberg Lab. for Cardiovasc. Res., Göteborg University, Sahlgrenska University Hospital, Göteborg, Sweden.
    Effect of phenotype on the transcription of the genes for platelet-derived growth factor (PDGF) isoforms in human smooth muscle cells, monocyte-derived macrophages, and endothelial cells in vitro1997In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 17, no 11, p. 2897-2903Article in journal (Refereed)
    Abstract [en]

    Proliferation of arterial smooth muscle cells (ASMCs) contributes considerably to enlargement of the arterial wall during atherosclerosis. The platelet-derived growth factor (PDGF) is a well-known mitogen and chemoattractant for ASMCs. Quantitative reverse transcription-polymerase chain reaction showed that cells appearing in atherosclerotic lesions, such as ASMCs, endothelial cells, and monocytes/macrophages, expressed mRNAs for both PDGF A and B chains in vitro, with the highest expression in endothelial cells. On proliferation, ASMCs and endothelial cells upregulated PDGF A mRNA. Differentiation of macrophages increased the amount of both mRNAs. Thus, the regulation of PDGF A- and B-chain expression depends on cell types and phenotypic states of the cells, which have also been found in vivo in human atherosclerotic lesions. PDGF A can be produced as short and long isoforms. The latter binds with high affinity to glycosaminoglycans. Irrespective of phenotype, only the minor part of total PDGF A mRNA consisted of the long variant in ASMCs, while endothelial cells produced 40% of total PDGF A as the long form. The differentiation of macrophages increased the production of the long PDGF A mRNA from 10% to 40%. Thus, increasing numbers of stimulated cells in the atherosclerotic lesion may increase the transcription of PDGF isoforms, and particularly of the long PDGF A isoform. Together with increasing amounts of ASMC-derived proteoglycans in developing lesions, this may contribute to accumulation of PDGF in the arterial wall matrix, resulting in prolonged stimulation of ASMCs.

  • 9.
    Krettek, Alexandra
    et al.
    Nordic School of Public Health, Gothenburg, Sweden / Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Sjöberg, Sara
    Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    CD44 - a new cardiovascular drug target or merely an innocent bystander?2009In: Cardiovascular & hematological disorders drug targets, ISSN 2212-4063, Vol. 9, no 4, p. 293-302Article, review/survey (Refereed)
    Abstract [en]

    CD44, short for cluster of differentiation 44, is an adhesion molecule of the hyaluronate receptor family. Expressed on the surface of most vertebrate cells, it functions as a receptor for several extracellular matrix components, e.g., hyaluronan, collagen, laminin, fibronectin, and osteopontin. CD44 has in recent years been intensively studied in connection with different forms of cancer, where CD44 may regulate invasiveness and tumor progression. Although major functions involve adhesion and migration, CD44 also affects leukocyte homing and recruitment, phagocytosis, matrix remodeling, proliferation, and apoptosis. As such, CD44 is an interesting putative molecule in cardiovascular drug therapy. Accumulating evidence from human studies point to CD44 as involved in inflammatory diseases such as atherosclerosis and human abdominal aneurysms. To date, several animal studies have shown that the role of CD44 in atherogenesis may vary depending on experimental model. In this Review, we trace CD44 and its potential role in the context of cardiovascular diseases by highlighting both human and animal studies that may help us understand; is CD44 a new cardiovascular drug target or merely an innocent bystander?

  • 10.
    Krettek, Alexandra
    et al.
    Brigham and Women's Hospital, Harvard Medical School, Boston, United States.
    Sukhova, Galina K.
    Brigham and Women's Hospital, Harvard Medical School, Boston, United States.
    Libby, Peter
    Brigham and Women's Hospital, Harvard Medical School, Boston, United States.
    Elastogenesis in human arterial disease: A role for macrophages in disordered elastin synthesis2003In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 23, no 4, p. 582-587Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Elastin, an extracellular matrix protein, constitutes about 30% of the dry weight of the arteries. Elastolysis induced by inflammatory processes is active in chronic arterial diseases. However, elastogenesis in arterial diseases has received little attention. In this work we hypothesized that disordered elastogenesis is active in matrix remodeling in atheroma and abdominal aortic aneurysm (AAA).

    METHODS AND RESULTS: Human AAA and atheroma have 4- to 6-fold more tropoelastin protein than nondiseased arteries. The smooth muscle cell-containing media and fibrous cap of atherosclerotic arteries contain ordered mature elastin, whereas macrophage (MPhi)-rich regions often have disorganized elastic fibers. Surprisingly, in addition to smooth muscle cells, MPhis in diseased arteries also produce the elastin precursor tropoelastin, as shown by double immunostaining, in situ hybridization, and reverse transcription-polymerase chain reaction for tropoelastin mRNA. Cultured monocyte-derived MPhis can express the elastin gene. AAA have 9-fold but atheroma only 1.6-fold lower levels of desmosine, a marker for mature cross-linked elastin, than normal arteries.

    CONCLUSIONS: This study demonstrates ongoing but often ineffective elastogenesis in arterial disease and establishes human macrophages as a novel source for this important matrix protein. These results have considerable import for understanding mechanisms of extracellular matrix remodeling in arterial diseases.

  • 11.
    Krettek, Alexandra
    et al.
    Harvard Medical School, Boston, Massachusetts.
    Sukhova, Galina K.
    Schönbeck, Uwe
    Libby, Peter
    Enhanced expression of CD44 variants in human atheroma and abdominal aortic aneurysm: possible role for a feedback loop in endothelial cells2004In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 165, no 5, p. 1571-1581Article in journal (Refereed)
    Abstract [en]

    CD44, a polymorphic hyaluronate receptor, may participate in chronic inflammation. We hypothesized that CD44 variants contribute to the development of arterial diseases. CD44 levels vary in normal and diseased arterial tissues in the following order: unaffected arteries < fibrous plaques < or = abdominal aortic aneurysm < atheromatous plaques; and correlate with macrophage content. Furthermore, plaque microvessels express CD44, and anti-CD44v3 or anti-CD44v6 treatment reduces endothelial cell proliferation but not apoptosis in vitro, suggesting functionality of these receptors. Endothelial cells express CD44H and CD44v6 after exposure to interleukin-1beta and tumor necrosis factor-alpha. Macrophages, a major source of abundant CD44 in vitro, express not only CD44H but also variants CD44v4/5, CD44v6, and CD44v7/8, isoforms distinctively regulated by proinflammatory cytokines. Several proinflammatory cytokines induce shedding of CD44 from the surface of macrophages and endothelial cells. Soluble CD44 stimulates the expression and release of interleukin-1beta from endothelial cells, suggesting a positive feedback loop of this cytokine. By demonstrating augmented expression of CD44 and variants within human atheroma and in abdominal aortic aneurysm as well as the vascular cell release of sCD44, a process regulated by proinflammatory cytokines, this study provides new insights on the functions of CD44 in arterial diseases.

  • 12.
    Krettek, Alexandra
    et al.
    Wallenberg Laboratory for Cardiovascular Research, Göteborg University, Sahlgrenska University Hospital, Göteborg, Sweden.
    Östergren-Lundén, G.
    Wallenberg Laboratory for Cardiovascular Research, Göteborg University, Sahlgrenska University Hospital, Göteborg, Sweden.
    Fager, G.
    Wallenberg Laboratory for Cardiovascular Research, Göteborg University, Sahlgrenska University Hospital, Göteborg, Sweden.
    Rosmond, C.
    Wallenberg Laboratory for Cardiovascular Research, Göteborg University, Sahlgrenska University Hospital, Göteborg, Sweden.
    Bondjers, G.
    Wallenberg Laboratory for Cardiovascular Research, Göteborg University, Sahlgrenska University Hospital, Göteborg, Sweden.
    Lustig, F.
    Wallenberg Laboratory for Cardiovascular Research, Göteborg University, Sahlgrenska University Hospital, Göteborg, Sweden.
    Expression of PDGF receptors and ligand-induced migration of partially differentiated human monocyte-derived macrophages. Influence of IFN-gamma and TGF-beta2001In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 156, no 2, p. 267-275Article in journal (Refereed)
    Abstract [en]

    In the early atherosclerotic lesion, monocytes accumulate at sites of inflammation and endothelial injury. Platelet-derived growth factor (PDGF), produced for example by macrophages, is a chemoattractant for smooth muscle cells and possibly also for macrophages. During early differentiation into macrophages, human monocytes (early hMDM) showed lower expression of PDGF alpha-receptor (PDGF-Ralpha) than beta-receptor (PDGF-Rbeta) mRNA. Early hMDM showed increased random motility (chemokinesis) in the presence of PDGF of the long (BB(L)) but not short (BB(S)) B-chain homodimer. Neither PDGF-AA(S) nor PDGF-AA(L) affected early hMDM motility. Since increased cytokine levels accompany inflammation, the influence of interferon-gamma (IFN-gamma) and transforming growth factor-beta (TGF-beta) on PDGF-R expression and migratory response were studied. Only PDGF-Ralpha mRNA was highly upregulated by IFN-gamma. TGF-beta only had minor effects on receptor mRNAs. Upregulation of PDGF-Ralpha levels by IFN-gamma was accompanied by significantly increased migration (chemotaxis) towards PDGF-AA(L) only. Consequently, IFN-gamma modulates PDGF-Rs expression in early hMDM and, subsequently, the chemotactic activity of PDGF-AA(L) on IFN-gamma-stimulated early hMDM. This suggests that PDGF-AA(L) may be involved in attracting activated monocytes to sites of inflammation and injury.

  • 13.
    Morelli, Paula I.
    et al.
    Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Academy, Göteborg University, Göteborg, Sweden / Wallenberg Laboratory, Sahlgrenska University Hospital, Göteborg, Sweden.
    Martinsson, Sofia
    Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Academy, Göteborg University, Göteborg, Sweden.
    Östergren-Lundén, Gunnel
    Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Academy, Göteborg University, Göteborg, Sweden.
    Fridén, Vincent
    Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Academy, Göteborg University, Göteborg, Sweden.
    Moses, Jonatan
    Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Academy, Göteborg University, Göteborg, Sweden.
    Bondjers, Göran
    Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Academy, Göteborg University, Göteborg, Sweden.
    Krettek, Alexandra
    Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Academy, Göteborg University, Göteborg, Sweden.
    Lustig, Florentyna
    Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Academy, Göteborg University, Göteborg, Sweden.
    IFN gamma regulates PDGF-receptor alpha expression in macrophages, THP-1 cells, and arterial smooth muscle cells2006In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 184, no 1, p. 39-47Article in journal (Refereed)
    Abstract [en]

    The recruitment of monocyte-derived macrophages (MDMs) and arterial smooth muscle cells (ASMCs) contributes to inflammation and development of intimal hyperplasia during atherosclerosis. Platelet-derived growth factor (PDGF) is a potent mitogen for SMC, signalling through PDGF-receptor subunits alpha (Ralpha) and beta (Rbeta). We have previously found that interferon gamma (IFNgamma) upregulates PDGF-Ralpha mRNA expression in human MDM (hMDM) which causes an increased migration towards PDGF. In the present study, we found that IFNgamma mediated an upregulation of PDGF-Ralpha mRNA also in THP-1 cells. The induction of PDGF-Ralpha in both hMDM and THP-1 cells was caused by STAT1 binding to the PDGF-Ralpha promoter. In human ASMCs, IFNgamma again stimulated a transient STAT1-binding to the PDGF-Ralpha promoter. However, this was not followed by an upregulation of PDGF-Ralpha mRNA. IFNgamma-stimulation resulted in augmented expression of PDGF-Ralpha protein in differentiated hMDM. Early hMDM only expressed an immature and not fully glycosylated form of the PDGF-Ralpha protein. In contrast, THP-1 cells did not synthesize PDGF-Ralpha protein, implying further posttranscriptional inhibition. Our results contribute to a better understanding of the complex regulation of PDGF-Ralpha expression and how proinflammatory factors may contribute to PDGF-related hyperplasia in vascular diseases.

  • 14.
    Rydberg, Ellen Knutsen
    et al.
    Wallenberg Lab. for Cardiovasc. Res., Sahlgrenska University Hospital, Göteborg, Sweden.
    Krettek, Alexandra
    Wallenberg Lab. for Cardiovasc. Res., Sahlgrenska University Hospital, Göteborg, Sweden.
    Ullström, Christina
    Wallenberg Lab. for Cardiovasc. Res., Sahlgrenska University Hospital, Göteborg, Sweden.
    Ekström, Karin
    Wallenberg Lab. for Cardiovasc. Res., Sahlgrenska University Hospital, Göteborg, Sweden.
    Svensson, Per-Arne
    Res. Ctr. for Endocrinol./Metabolism, Sahlgrenska Univ. Hospital, Göteborg, Sweden.
    Carlsson, Lena M. S.
    Res. Ctr. for Endocrinol./Metabolism, Sahlgrenska Univ. Hospital, Göteborg, Sweden.
    Jönsson-Rylander, Ann-Cathrine
    Molecular Pharmacology and DMPK, AstraZeneca R and D, Mölndal, Sweden.
    Hansson, Göran I.
    Bioanalytical Chemistry, AstraZeneca R and D, Mölndal, Sweden.
    McPheat, William
    Molecular Pharmacology and DMPK, AstraZeneca R and D, Mölndal, Sweden.
    Wiklund, Olov
    Wallenberg Lab. for Cardiovasc. Res., Sahlgrenska University Hospital, Göteborg, Sweden.
    Ohlsson, Bertil G.
    Wallenberg Lab. for Cardiovasc. Res., Sahlgrenska University Hospital, Göteborg, Sweden.
    Hultén, Lillemor Mattsson
    Wallenberg Lab. for Cardiovasc. Res., Sahlgrenska University Hospital, Göteborg, Sweden.
    Hypoxia increases LDL oxidation and expression of 15-lipoxygenase-2 in human macrophages2004In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 24, no 11, p. 2040-2045Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Macrophage-mediated oxidation of low-density lipoprotein (LDL) by enzymes, such as the lipoxygenases, is considered of major importance for the formation of oxidized LDL during atherogenesis. Macrophages have been identified in hypoxic areas in atherosclerotic plaques.

    METHODS AND RESULTS: To investigate the role of hypoxia in macrophage-mediated LDL oxidation, we incubated human monocyte-derived macrophages with LDL under normoxic (21% O2) or hypoxic (0% O2) conditions. The results showed that hypoxic macrophages oxidized LDL to a significantly higher extent than normoxic cells. Interestingly, the mRNA and protein expression of 15-lipoxygenase-2 (15-LOX-2) as well as the activity of this enzyme are elevated in macrophages incubated at hypoxia. Both the unspliced 15-LOX-2 and the spliced variant 15-LOX-2sv-a are found in macrophages. In addition, 15-LOX-2 was identified in carotid plaques in some macrophage-rich areas but was only expressed at low levels in nondiseased arteries.

    CONCLUSIONS: In summary, these observations show for the first time that 15-LOX-2 is expressed in hypoxic macrophages and in atherosclerotic plaques and suggest that 15-LOX-2 may be one of the factors involved in macrophage-mediated LDL oxidation at hypoxia.

  • 15.
    Sjöberg, Sara
    et al.
    Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Eriksson, Einar E.
    Dept. of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
    Tivesten, Åsa
    Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Carlsson, Annelie
    Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Klasson, Anna
    Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Levin, Max
    Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Borén, Jan
    Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Krettek, Alexandra
    Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden / Nordic School of Public Health, Gothenburg, Sweden.
    CD44-deficiency on hematopoietic cells limits T-cell number but does not protect against atherogenesis in LDL receptor-deficient mice2009In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 206, no 2, p. 369-374Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Vascular and inflammatory cells express adhesion molecule CD44. We demonstrated previously that enhanced CD44 localizes in human atherosclerotic lesions. Apolipoprotein E/cd44 double-deficient mice and apolipoprotein E-deficient mice transplanted with CD44-deficient bone marrow (BM) exhibit reduced atherosclerosis. Since CD44 is a novel factor in atherogenesis, it is imperative that it is investigated in more than one animal model to conclusively determine its role in this particular disease pathology. To test the hypothesis that CD44 expressed by hematopoietic cells plays a critical role in atherogenesis in the low density lipoprotein (LDL) receptor-deficient mouse model, we performed BM reconstitution experiments.

    METHODS: Lethally irradiated LDL receptor-deficient mice were transplanted with either CD44-deficient or wild-type BM. Beginning 10 weeks after successful reconstitution, mice consumed a cholesterol-enriched atherogenic diet for 6 or 11 weeks.

    RESULTS: Surprisingly, CD44-deficiency on BM-derived inflammatory cells did not affect lesion size. Additionally, neither group displayed differences in smooth muscle cell, macrophage, collagen, or elastin content as well as lipoprotein levels. However, lesions in CD44-deficient BM-recipient mice contained fewer T-cells compared to wild-type BM mice. Interestingly, CD44-deficient T-cells expressed less chemokine receptor-5 mRNA. Furthermore, in vivo leukocyte adhesion decreased in CD44-deficient mice compared to wild-type mice.

    CONCLUSION: This study surprisingly revealed that atherogenesis does not require CD44 expression on hematopoietic cells in the LDL receptor-deficient mouse model. However, CD44 promotes T-cell recruitment, downregulates chemokine receptor-5, and participates critically in leukocyte adhesion in vivo. Consequently, the anti-atherogenic role of CD44 may require CD44-deficiency on cell types other than inflammatory cells in the LDL receptor-deficient mouse model.

  • 16.
    Sjöberg, Sara
    et al.
    Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Academy at Göteborg University, Göteborg, Sweden.
    Fogelstrand, Linda
    Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Academy at Göteborg University, Göteborg, Sweden.
    Hulthe, Johannes
    Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Academy at Göteborg University, Göteborg, Sweden.
    Fagerberg, Björn
    Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Academy at Göteborg University, Göteborg, Sweden.
    Krettek, Alexandra
    Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Academy at Göteborg University, Göteborg, Sweden / Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital, Göteborg, Sweden.
    Circulating soluble CD44 is higher among women than men and is not associated with cardiovascular risk factors or subclinical atherosclerosis2005In: Metabolism: Clinical and Experimental, ISSN 0026-0495, E-ISSN 1532-8600, Vol. 54, no 2, p. 139-141Article in journal (Refereed)
    Abstract [en]

    In the present study, the associations between the plasma concentration of soluble CD44 (sCD44), sex, cardiovascular risk factors, and ultrasound-assessed measures of carotid atherosclerosis were examined in 2 groups of 61- and 64-year-old men and women from population-based samples. Women had higher levels of circulating sCD44 than men. There were no associations between sCD44 and cardiovascular risk factors or subclinical atherosclerosis.

  • 17.
    Theurich, Melissa Ann
    et al.
    LMU - Ludwig-Maximilians-Universität Munich, Div. Metabolic and Nutritional Medicine, Dr. von Hauner Children's Hospital, Munich, Germany.
    Davanzo, Riccardo
    Department of Mother and Child Health, ASM-Matera and Task Force on Breastfeeding, MOH, Rome, Italy.
    Busck-Rasmussen, Marianne
    Danish Committee for Health Education, Copenhagen, Denmark.
    Díaz-Gómez, N. Marta
    Instituto de Tecnologías Biomédicas (ITB) and Centro de Investigaciones Biomédicas de Canarias (CIBICAN), Universidad de La Laguna, Spain.
    Brennan, Christine
    Breastfeeding Promotion Foundation, Bern, Switzerland.
    Kylberg, Elisabeth
    University of Skövde, School of Health and Education. University of Skövde, Health and Education.
    Bærug, Anne
    Norwegian National Advisory Unit on Breastfeeding, Oslo, Norway.
    McHugh, Laura
    Health Service Executive, Ennis, Ireland.
    Weikert, Cornelia
    German Federal Institute for Risk Assessment, Department of Food Safety, Berlin, Germany.
    Abraham, Klaus
    German Federal Institute for Risk Assessment, Department of Food Safety, Berlin, Germany.
    Koletzko, Berthold
    LMU - Ludwig-Maximilians-Universität Munich, Div. Metabolic and Nutritional Medicine, Dr. von Hauner Children's Hospital, Munich, Germany.
    Breastfeeding Rates and Programs in Europe: A Survey of 11 National Breastfeeding Committees and Representatives2019In: Journal of Pediatric Gastroenterology and Nutrition - JPGN, ISSN 0277-2116, E-ISSN 1536-4801, Vol. 68, no 3, p. 400-407Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Among the world's regions, the WHO European Region has the lowest rates of exclusive breastfeeding at age 6 months with around 25%. Low rates and early cessation of breastfeeding have important adverse health consequences for women, infants and young children. Protecting, promoting and supporting breastfeeding are a public health priority.

    OBJECTIVES: National breastfeeding data and monitoring systems among selected European countries and the WHO European Region are compared. Mechanisms for the support, protection and promotion of breastfeeding are reviewed and successes and challenges in implementation of national programs are presented.

    METHODS: National representatives of national breastfeeding committees and initiatives in eleven European countries, including Belgium, Croatia, Denmark, Germany, Ireland, Italy, The Netherlands, Norway, Spain, Sweden and Switzerland, participated in a standardized survey. Results are evaluated and compared in a narrative review.

    RESULTS: Variation exists in Europe on breastfeeding rates, methodology for data collection and mechanisms for support, protection and promotion of breastfeeding. Directly after birth, between 56 and 98 % of infants in all countries were reported to receive any human milk, and at 6 months 38-71% and 13-39 % of infants to be breastfed or exclusively breastfed, respectively. National plans addressing breastfeeding promotion, protection and support exist in 6 of the 11 countries.

    CONCLUSIONS: National governments should commit to evidence-based breastfeeding monitoring and promotion activities, including financial and political support, to improve breastfeeding rates in the Europe. Renewed efforts for collaboration between countries in Europe, including a sustainable platform for information exchange, are needed.

  • 18.
    Östergren-Lundén, Gunnel
    et al.
    Wallenberg Laboratory for Cardiovascular Research, The Sahlgrenska Academy at Göteborg University, Göteborg, Sweden.
    Olivas, Raquel G.
    Departamento de Biologı́a Celular, Universitat de Barcelona, Barcelona, Spain.
    Eftekhari, Pierre
    UPR9021 C.N.R.S., Immunologie et Chimie Thérapeutiques, I.B.M.C., Strasbourg, France.
    Krettek, Alexandra
    Wallenberg Laboratory for Cardiovascular Research, The Sahlgrenska Academy at Göteborg University, Göteborg, Sweden.
    Sanjuan, Xavier
    Departamento de Biologı́a Celular, Universitat de Barcelona, Barcelona, Spain.
    Fager, Gunnar
    Wallenberg Laboratory for Cardiovascular Research, The Sahlgrenska Academy at Göteborg University, Göteborg, Sweden.
    Vilaró, Senén
    Departamento de Biologı́a Celular, Universitat de Barcelona, Barcelona, Spain.
    Lustig, Florentyna
    Wallenberg Laboratory for Cardiovascular Research, The Sahlgrenska Academy at Göteborg University, Göteborg, Sweden.
    Hoebeke, Johan
    UPR9021 C.N.R.S., Immunologie et Chimie Thérapeutiques, I.B.M.C., Strasbourg, France.
    Characterisation and application of antibodies specific for the long platelet-derived growth factor A and B chains2004In: International Journal of Biochemistry and Cell Biology, ISSN 1357-2725, E-ISSN 1878-5875, Vol. 36, no 11, p. 2226-2241Article in journal (Refereed)
    Abstract [en]

    The platelet-derived growth factor (PDGF) family comprises important mitogens for mesenchymal cells. The active dimeric form of PDGF consists of four structurally related A, B, C, and D chains. All PDGF-variants bind to PDGF-receptors. The A and B chains occur with and without basic C-terminal amino acid extensions as long (A(L) and B(L)) and short (A(S) and B(S)) isoforms. PDGF-A and -B form homo- or heterodimers. The biological relevance of short and long isoforms is unknown, although it may relate to different affinities for glycosaminoglycans of the cell glycocalix and intercellular matrix. Commercially available anti-PDGF-A and anti-PDGF-B antibodies cannot discriminate between the short and the long isoforms. Thus, to investigate the function of the long and short isoforms, we raised antibodies specific for the long A and B chain isoforms. The antibodies were affinity-purified and their properties analysed by surface plasmon resonance. Inhibition studies with different PDGF homodimers and dot-blot studies proved their high specificity for the respective isoforms. Both antibodies recognised the target PDGF homodimers complexed to the glycocalix of human arterial smooth muscle cells and human monocyte-derived macrophages. By using these specific antibodies, we were able to confirm at the protein level the synthesis of PDGF-A and -B during differentiation of human monocyte-derived macrophages and to demonstrate the presence of the PDGF-A(L) and PDGF-B(L) isoforms in human arterial tissue.

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