Smooth muscle cell-specific SOCS3 deficiency promote pericardial fibrosis and diastolic dysfunction in aging mice

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
T Yanai ◽  
H Yasukawa ◽  
K Mawatari ◽  
T Sasaki ◽  
J Takahashi ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Growth Factor ◽  
Smooth Muscle Cells ◽  
Smooth Muscle Cell ◽  
Diastolic Dysfunction ◽  
Interstitial Fibrosis ◽  
Muscle Cells ◽  
Left Ventricular ◽  
Funding Source ◽  
Wild Type

Abstract Background Suppressor of cytokine signaling-3 (SOCS3) is a cytokine-inducible negative regulator of signal transducer and activator of transcription-3 (STAT3) signaling pathway. We have previously shown that cardiac-specific SOCS3 deficiency spontaneously develop cardiac dysfunction with advanced age. However, the role of SOCS3 in smooth muscle cells in cardiovascular pathophysiology remains elusive. In this study, we determined whether STAT3 and SOCS3 in smooth muscle cells would play a role in cardiovascular pathophysiology. Methods and results To target inactivation of the SOCS3 gene to smooth muscle cells, SOCS3-flox mice were bred with transgenic mice expressing Cre recombinase under control of the mouse SM22-α promoter (sm-SOCS3-KO mice). Left ventricular weight to body weight ratio was significantly increased in sm-SOCS3-KO mice compared with wild-type mice at 12 months of age (p<0.05). Echocardiographic analyses of smSOCS3-KO mice showed significantly increased left ventricular diastolic dysfunction compared with wild-type from 12 months of age (p<0.05). Sirius-red staining revealed that thickness of pericardium and cardiac interstitial fibrosis in sm-SOCS3-KO mice were markedly greater compared with wild-type mice at 12 months of age (p<0.05). Western blot analyses showed that phosphorylated STAT3 was significantly increased in sm-SOCS3-KO hearts compared with wild-type mice at 12 months of age (p<0.05), whereas no significant differences were observed at 2 months of age. To investigate the mechanism that gave rise to promoted cardiac fibrosis and diastolic dysfunction during aging in sm-SOCS3-KO, we conducted a real-time PCR array analysis for fibrosis. The expression of pro-fibrotic CTGF (connective tissue growth factor), PDGFb (platelet growth factor-b), and TGF (transforming growth factor) family genes including TGFb1, TGFb2, and TGFb3, were significantly higher in sm-SOCS3-KO hearts than those in wild-type at 6 months of age. Conclusion Thus, smooth muscle cell-specific SOCS3 deletion induces increased pericardial fibrosis, cardiac interstitial fibrosis, and increased diastolic dysfunction in aging mice, possibly through the augmentation of pro-fibrotic growth factors. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Grant JSPS KAKENHI

Effects of smooth muscle cell derived growth factor (SDGF) in combination with other growth factors on smooth muscle cells

1989 ◽  
Vol 78 (1) ◽  
pp. 61-67 ◽  
Author(s):  
Nobuhiro Morisaki ◽  
Noriyuki Koyama ◽  
Seijiro Mori ◽  
Tetsuto Kanzaki ◽  
Tomoko Koshikawa ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Growth Factors ◽  
Growth Factor ◽  
Smooth Muscle Cells ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Muscle Cells

Expression and control of C-type natriuretic peptide in rat vascular smooth muscle cells

2002 ◽  
Vol 282 (1) ◽  
pp. R156-R165 ◽  
Author(s):  
Geoffrey E. Woodard ◽  
Juan A. Rosado ◽  
John Brown
Keyword(s):  
Cell Proliferation ◽  
Smooth Muscle ◽  
Growth Factor ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Smooth Muscle Cell ◽  
Natriuretic Peptide ◽  
Vascular Smooth Muscle Cells ◽  
Muscle Cells ◽  
Natriuretic Peptide Receptors

C-type natriuretic peptide (CNP) is a member of the natriuretic peptide family mainly distributed in the central nervous system. CNP is also produced and secreted by the endothelium and inhibits vascular smooth muscle cell proliferation. We have reported that endothelial damage stimulates only transiently vascular smooth muscle cell proliferation in arteries due to the development of an autocrine neointimal system for CNP that modulates neointimal growth. The present study demonstrates the production and secretion of CNP in rat vascular smooth muscle cells in the absence of endothelium. In addition, these cells express atrial natriuretic peptide (ANP) and the natriuretic peptide receptors A, B, and C. The production and secretion of CNP in vascular smooth muscle cells is stimulated by transforming growth factor-β, whereas basic fibroblast growth factor plays an inhibitory role. These data show that ANP and mainly CNP are coexpressed with the natriuretic peptide receptors in rat vascular smooth muscle cells. This provides evidence for a vascular natriuretic peptide autocrine system of physiological relevance in these cells.

Heparin inhibits Na(+)-H+ exchange in vascular smooth muscle cells

1990 ◽  
Vol 258 (1) ◽  
pp. C46-C53 ◽  
Author(s):  
R. Zaragoza ◽  
K. M. Battle-Tracy ◽  
N. E. Owen
Keyword(s):  
Cell Proliferation ◽  
Smooth Muscle ◽  
Growth Factor ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Smooth Muscle Cell ◽  
Vascular Smooth Muscle Cells ◽  
Muscle Cell ◽  
Vascular Smooth Muscle Cell ◽  
Muscle Cells

Vascular smooth muscle cell proliferation has been shown to be an important factor in atheromatous plaque formation, hypertrophy associated with essential hypertension, and failure of balloon angioplasty procedures. Investigators have shown that a number of different agents stimulate vascular smooth muscle cell proliferation, including epidermal growth factor, platelet-derived growth factor, angiotensin II, and catecholamines. Previously, we have demonstrated that these agents also cause immediate changes in ion transport and second messenger generation in vascular smooth muscle cells. We have proposed that these immediate changes may be linked to each other and to cell proliferation. In contrast to the many agents that have been shown to stimulate vascular smooth muscle cell proliferation, only a few agents (e.g., heparin sodium or transforming growth factor-beta) have been shown to inhibit vascular smooth muscle cell proliferation. In the present study we have investigated whether heparin inhibits serum- or growth factor-stimulated changes in ion transport and second messenger generation in vascular smooth muscle cells. We found that heparin inhibits serum- or growth factor-stimulated Na(+)-H+ exchange in a concentration-dependent manner that is not dependent on the ability of heparin to function as an anticoagulant agent. In addition, other glycosaminoglycans were not found to be inhibitory, and the inhibitory effects of heparin were discovered to be limited to vascular smooth muscle cells. Heparin does not appear to be acting by binding to growth factors, or by directly inhibiting the Na(+)-H+ exchange protein. However, heparin did inhibit serum- or growth factor-stimulated inositol trisphosphate release and calcium mobilization.(ABSTRACT TRUNCATED AT 250 WORDS)

Lack of PI 3-kinase isoform p110alpha in smooth muscle cells impairs aortic wall homoeostasis and thus promotes aortic aneurysm formation

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Vantler ◽  
E Berghausen ◽  
M Zierden ◽  
M Mollenhauer ◽  
D Mehrkens ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Aortic Aneurysm ◽  
Smooth Muscle Cells ◽  
Aortic Wall ◽  
Muscle Cells ◽  
Vascular Wall ◽  
Aortic Diameter ◽  
Funding Source ◽  
Wild Type ◽  
Tunica Media

Abstract Background In smooth muscle cells (SMCs), the PI 3-kinase isoform p110α mediates receptor tyrosine kinase dependent proliferation, chemotaxis and cell survival. Since mice, harbouring a smooth muscle specific p110α deficiency (SM-p110α−/−), display reduced vascular wall thickness, we hypothesized that SM-p110α−/− mice might be prone to aortic aneurysm (AA) formation. The pathogenesis of AA is characterized by increased dedifferentiation of SMCs, extracellular matrix (ECM) degeneration and inflammation in the aortic wall. Herein, we investigated how p110α-dependent signal transduction in SMCs affects these processes. Methods and results We examined AA formation in SM-p110α−/− mice and wild-type littermates using the “porcine pancreatic elastase” (PPE) AA model. PPE was infused into the infrarenal aorta to induce AA formation. Ultrasound examination of the aorta revealed an enlarged aortic diameter in all PPE-treated mice. The aortic diameter in SM-p110α−/− mice (0.46±0.12 mm) was significantly increased compared to wild-type animals (0.18±0.03 mm, p<0.01). These data indicate a protective function of p110α in AA formation. Immunocytochemical examination of the tunica media of PPE-perfused SM-p110α−/− mice revealed significantly increased infiltration of CD45+ leukocytes. In particular, the number of MOMA-2+ monocytes / macrophages in the vessel wall was significantly increased indicating elevated inflammation of the aortic wall during AA progression in comparison to wild-type control mice. Ultrastructural analysis of aortic wall morphology in SM-p110α−/− mice using transmission electron microscopy (TEM) showed a deranged tunica media and increased apoptotic cell death. In addition, the media thickness in the abdominal aorta was significantly reduced in SM-p110α−/− mice (29.0±3.1 μm vs. 42.5±4.1 μm). Western blots demonstrated a reduced elastin and fibrillin expression in SMCs from SM-p110α−/− mice. p110α−/− SMCs showed significantly reduced expression of differentiation markers SM-α-actin and SM-MHC. In addition, aortic p110α-deficient SMCs were significantly impaired in their ability to proliferate and migrate. These findings indicate that p110α−/− SMCs are neither differentiated nor dedifferentiated and have therefore largely lost their plasticity. Consequently, p110α deficiency significantly diminished responsiveness of aortic rings to vasodilator acetylcholine and NO-donor nitroglycerin, further indicating impaired contractility of SMCs. Mechanistically, we demonstrated that PDGF and insulin induced phosphorylation and inactivation of key regulators of SMC differentiation and dedifferentiation, Foxo4 and GSK3b, respectively, were abrogated in p110α−/− SMCs. Conclusion These data show that deficiency of p110α in SMCs promotes the formation and progression of AA. Causative are impaired SMC plasticity and ECM homeostasis as well as inflammatory processes in the vascular wall. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Deutsche Forschungsgemeinschaft (DFG)

Involvement of Cyclooxygenase- and Lipoxygenase-Mediated Conversion of Arachidonic Acid in Controlling Human Vascular Smooth Muscle Cell Proliferation

1990 ◽  
Vol 63 (02) ◽  
pp. 291-297 ◽  
Author(s):  
Herm-Jan M Brinkman ◽  
Marijke F van Buul-Worteiboer ◽  
Jan A van Mourik
Keyword(s):  
Cell Proliferation ◽  
Arachidonic Acid ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Vascular Smooth Muscle Cell ◽  
Muscle Cells ◽  
Smooth Muscle Cell Proliferation

SummaryWe observed that the growth of human umbilical arterysmooth muscle cells was inhibited by the phospholipase A2 inhibitors p-bromophenacylbromide and mepacrine. Thesefindings suggest that fatty acid metabolism might be integrated in the control mechanism of vascular smooth muscle cell proliferation. To identify eicosanoids possibly involved in this process, we studied both the metabolism of arachidonic acid of these cells in more detail and the effect of certain arachidonic acid metabolites on smooth muscle cells growth. We found no evidence for the conversion of arachidonic acid via the lipoxygenase pathway. In contrast, arachidonic acid was rapidly converted via the cyclooxy-genase pathway. The following metabolites were identified: prostaglandin E2 (PGE2), 6-keto-prostaglandin F1α (6-k-PGF1α), prostaglandin F2α (PGF2α), 12-hydroxyheptadecatrienoic acid (12-HHT) and 11-hydroxyeicosatetetraenoic acid (11-HETE). PGE2 was the major metabolite detected. Arachidonic acid metabolites were only found in the culture medium, not in the cell. After synthesis, 11-HETE was cleared from the culture medium. We have previously reported that PGE2 inhibits the serum-induced [3H]-thymidine incorporation of growth-arrested human umbilical artery smooth muscle cells. Here we show that also 11-HETEexerts this inhibitory property. Thus, our data suggeststhat human umbilical artery smooth muscle cells convert arachidonic acid only via the cyclooxygenase pathway. Certain metabolites produced by this pathway, including PGE2 and 11-HETE, may inhibit vascular smooth muscle cell proliferation.

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