scholarly journals PDGF-induced vascular smooth muscle cell proliferation is associated with dysregulation of insulin receptor substrates

2011 ◽  
Vol 300 (6) ◽  
pp. C1375-C1385 ◽  
Author(s):  
Yan Zhao ◽  
Swarajit K. Biswas ◽  
Patrick H. McNulty ◽  
Mark Kozak ◽  
John Y. Jun ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Insulin Receptor ◽  
Serine Phosphorylation ◽  
Phenotypic Switching ◽  
Dependent Manner ◽  
Receptor Signaling ◽  
Vsmc Proliferation ◽  
Insulin Receptor Substrates ◽  
Insulin Receptor Signaling

In vascular smooth muscle cells (VSMCs), platelet-derived growth factor (PDGF) plays a major role in inducing phenotypic switching from contractile to proliferative state. Importantly, VSMC phenotypic switching is also determined by the phosphorylation state/expression levels of insulin receptor substrate (IRS), an intermediary signaling component that is shared by insulin and IGF-I. To date, the roles of PDGF-induced key proliferative signaling components including Akt, p70S6kinase, and ERK1/2 on the serine phosphorylation/expression of IRS-1 and IRS-2 isoforms remain unclear in VSMCs. We hypothesize that PDGF-induced VSMC proliferation is associated with dysregulation of insulin receptor substrates. Using human aortic VSMCs, we demonstrate that prolonged PDGF treatment led to sustained increases in the phosphorylation of protein kinases such as Akt, p70S6kinase, and ERK1/2, which mediate VSMC proliferation. In addition, PDGF enhanced IRS-1/IRS-2 serine phosphorylation and downregulated IRS-2 expression in a time- and concentration-dependent manner. Notably, phosphoinositide 3-kinase (PI 3-kinase) inhibitor (PI-103) and mammalian target of rapamycin inhibitor (rapamycin), which abolished PDGF-induced Akt and p70S6kinase phosphorylation, respectively, blocked PDGF-induced IRS-1 serine phosphorylation and IRS-2 downregulation. In contrast, MEK1/ERK inhibitor (U0126) failed to block PDGF-induced IRS-1 serine phosphorylation and IRS-2 downregulation. PDGF-induced IRS-2 downregulation was prevented by lactacystin, an inhibitor of proteasomal degradation. Functionally, PDGF-mediated IRS-1/IRS-2 dysregulation resulted in the attenuation of insulin-induced IRS-1/IRS-2-associated PI 3-kinase activity. Pharmacological inhibition of PDGF receptor tyrosine kinase with imatinib prevented IRS-1/IRS-2 dysregulation and restored insulin receptor signaling. In conclusion, strategies to inhibit PDGF receptors would not only inhibit neointimal growth but may provide new therapeutic options to prevent dysregulated insulin receptor signaling in VSMCs in nondiabetic and diabetic states.

Abstract 657: PDGF versus Fructose Dysregulation of Insulin Receptor Signaling in Vascular Smooth Muscle Cells: Pioglitazone-mediated Sensitization of Insulin Receptor Signaling is Associated with Diminished Vascular Smooth Muscle Cell Proliferation

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Islam Osman ◽  
Lakshman Segar
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Insulin Receptor ◽  
Vascular Smooth Muscle Cells ◽  
Insulin Signaling ◽  
Serine Phosphorylation ◽  
Receptor Signaling ◽  
Vsmc Proliferation ◽  
Insulin Receptor Signaling

Previous studies have shown that PDGF-induced activation of mTOR/p70S6kinase signaling is associated with dysregulation of insulin receptor substrates (IRS1 and IRS2) in vascular smooth muscle cells (VSMCs). In addition, pioglitazone (PIO, an antidiabetic drug) has been shown to inhibit mTOR/p70S6kinase signaling thereby suppressing PDGF-induced VSMC proliferation. The role of IRS1/IRS2 on proliferative signaling events has not yet been examined in VSMCs treated with fructose (an agent that induces insulin resistance) or PIO (an insulin sensitizer). In the present study, unlike PDGF treatment (48 hr) that enhanced IRS serine phosphorylation and diminished IRS2 expression, exposure of human aortic VSMCs to D-fructose (5.5 to 25 mM) for 48 hr resulted in a concentration-dependent increase in IRS1 serine phosphorylation (up to ~5-fold , n = 3), but without any changes in IRS2 protein expression. In D-fructose-treated VSMCs, Akt phosphorylation in response to acute insulin exposure (6 min) was markedly decreased (~69%, n = 3), suggesting that IRS1 serine phosphorylation alone is sufficient to dysregulate insulin receptor signaling. In addition, D-fructose treatment led to a further increase in PDGF-induced VSMC proliferation (~40%, n = 3). Furthermore, we examined the effects of PIO on PDGF-induced dysregulation of IRS in VSMCs. Notably, PIO treatment (30 μM, 48 hr) by itself led to an upregulation of IRS-2 expression (~2.5-fold) and also diminished PDGF-induced IRS1 serine phosphorylation (~63%). Under these conditions, PIO treatment resulted in significant inhibition of PDGF-induced cyclin D1 expression, Rb phosphorylation, and VSMC proliferation (~83%, n = 3). In conclusion, the present study reveals that dysregulated insulin signaling (by PDGF and fructose) is associated with enhanced VSMC proliferation, whereas insulin sensitization (by PIO) is associated with inhibition of VSMC proliferation. Together, these findings underscore the significance of intact insulin signaling toward limiting exaggerated VSMC proliferation in the vessel wall.

scholarly journals Exercise training improves muscle insulin resistance but not insulin receptor signaling in obese Zucker rats

2002 ◽  
Vol 92 (2) ◽  
pp. 736-744 ◽  
Author(s):  
Christine Y. Christ ◽  
Desmond Hunt ◽  
Joe Hancock ◽  
Rebeca Garcia-Macedo ◽  
Lawrence J. Mandarino ◽  
...  
Keyword(s):  
Exercise Training ◽  
Insulin Receptor ◽  
Glucose Uptake ◽  
Exercise Bout ◽  
Pi3 Kinase ◽  
Serine Phosphorylation ◽  
Zucker Rats ◽  
Receptor Signaling ◽  
Insulin Receptor Signaling ◽  
Obese Zucker Rats

Exercise training improves skeletal muscle insulin sensitivity in the obese Zucker rat. The purpose of this study was to investigate whether the improvement in insulin action in response to exercise training is associated with enhanced insulin receptor signaling. Obese Zucker rats were trained for 7 wk and studied by using the hindlimb-perfusion technique 24 h, 96 h, or 7 days after their last exercise training bout. Insulin-stimulated glucose uptake (traced with 2-deoxyglucose) was significantly reduced in untrained obese Zucker rats compared with lean controls (2.2 ± 0.17 vs. 5.4 ± 0.46 μmol · g−1 · h−1). Glucose uptake was normalized 24 h after the last exercise bout (4.9 ± 0.41 μmol · g−1 · h−1) and remained significantly elevated above the untrained obese Zucker rats for 7 days. However, exercise training did not increase insulin receptor or insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, phosphatidylinositol 3-kinase (PI3-kinase) activity associated with IRS-1 or tyrosine phosphorylated immunoprecipitates, or Akt serine phosphorylation. These results are consistent with the hypothesis that, in obese Zucker rats, adaptations occur during training that lead to improved insulin-stimulated muscle glucose uptake without affecting insulin receptor signaling through the PI3-kinase pathway.

scholarly journals Panax notoginsengSaponins Attenuate Phenotype Switching of Vascular Smooth Muscle Cells Induced by Notch3 Silencing

2015 ◽  
Vol 2015 ◽  
pp. 1-6 ◽  
Author(s):  
Nan Liu ◽  
Dazhi Shan ◽  
Ying Li ◽  
Hui Chen ◽  
Yonghong Gao ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Panax Notoginseng ◽  
Muscle Cells ◽  
Phenotypic Switching ◽  
Dependent Manner ◽  
Phenotype Switching ◽  
Dose Dependent

Panax notoginsengsaponins (PNS) could maintain vascular smooth muscle cells (VSMCs) in stable phenotypes so as to keep blood vessel elasticity as well as prevent failing in endovascular treatment with stent. Downregulation of Notch3 expression in VSMCs could influence the phenotype of VSMCs under pathologic status. However, whether PNS is able to attenuate the Notch3 silencing induced phenotype switching of VSMCs remains poorly understood. Primary human VSMCs were transfected with a plasmid containing a small interfering RNA (siRNA) against Notch3 and then exposed to different doses of PNS. The control groups included cells not receiving any treatment and cells transfected with a control siRNA. Phenotypic switching was evaluated by observing cell morphology with confocal microscopy, as well as examiningα-SM-actin, SM22α, and OPN using Western blot. Downregulated Notch3 with a siRNA induced apparent phenotype switching, as reflected by morphologic changes, decreased expression ofα-SM-actin and SM22αand increased expression of OPN. These changes were inhibited by PNS in a dose-dependent manner. The phenotype switching of VSMCs induced by Notch3 knockdown could be inhibited by PNS in a dose-dependent manner. Our study provided new evidence for searching effective drug for amending stability of atherosclerotic disease.

High glucose abolishes the antiproliferative effect of 17β-estradiol in human vascular smooth muscle cells

2002 ◽  
Vol 282 (4) ◽  
pp. E746-E751 ◽  
Author(s):  
Shanhong Ling ◽  
Peter J. Little ◽  
Maro R. I. Williams ◽  
Aozhi Dai ◽  
Kazuhiko Hashimura ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Dna Synthesis ◽  
High Glucose ◽  
Antiproliferative Effect ◽  
Dependent Manner ◽  
Vsmc Proliferation ◽  
Normal Glucose ◽  
17Β Estradiol ◽  
Pkc Β

We examined effects of 17β-estradiol (E2) on human vascular smooth muscle cell (VSMC) proliferation under normal (5 mmol/l) and high (25 mmol/l) glucose concentrations. Platelet-derived growth factor (PDGF) BB (20 ng/ml)-induced increases in DNA synthesis and proliferation were greater in high than normal glucose concentrations; the difference in DNA synthesis was abolished by a protein kinase C (PKC)-β inhibitor, LY-379196 (30 nmol/l). Western blotting showed that PKC-β1 protein increased in cells exposed to high glucose, whereas PKC-α protein and total PKC activity remained unchanged, compared with normal glucose cultures. In normal glucose, E2 (1–100 nmol/l) inhibited PDGF-induced DNA synthesis by 18–37% and cell proliferation by 16–22% in a concentration-dependent manner. The effects of E2 were blocked by the estrogen receptor (ER) antagonist ICI-182780, indicating ER dependence. In high glucose, the inhibitory effect of E2on VSMC proliferation was abolished but was restored in the presence of the PKC-β inhibitor LY-379196. Thus high glucose enhances human VSMC proliferation and attenuates the antiproliferative effect of E2 in VSMC via activation of PKC-β.

scholarly journals Inhibitory Effects of Genistein on Vascular Smooth Muscle Cell Proliferation Induced by Ox-LDL: Role of BKCa Channels

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Bing Bai ◽  
Nanjuan Lu ◽  
Wei Zhang ◽  
Jinghan Lin ◽  
Tingting Zhao ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Protein Expression ◽  
Molecular Mechanism ◽  
Vascular Diseases ◽  
Nuclear Antigen ◽  
Dependent Manner ◽  
Bkca Channels ◽  
Vsmc Proliferation

Background. Oxidized low-density lipoprotein (Ox-LDL) is a crucial pathogenic factor for vascular diseases, which can induce the proliferation of vascular smooth muscle cells (VSMCs). Genistein is the main component of soybean isoflavone. Genistein has a variety of pharmacological properties in the treatment of vascular diseases and a promising clinical application. Large-conductance calcium-activated potassium (BKCa) channels are the primary type of potassium channels in VSMCs, which regulate various biological functions of VSMCs. However, whether genistein exerts an antiproliferation effect on Ox-LDL-stimulated VSMCs remains unclear. The current study is aimed at elucidating the effect of genistein on the Ox-LDL-stimulated proliferation of VSMCs and its possible molecular mechanism, especially the electrophysiological mechanism related to BKCa channels. Methods. Monoculture VSMC was obtained by an acute enzyme-dispersing method. The proliferation of cells was measured by CCK-8, cell cycle, and proliferating cell nuclear antigen (PCNA) expression. The BKCa whole-cell currents were measured by patch-clamp. Results. Ox-LDL treatment induced the proliferation of VSMCs, upregulated the BKCa protein expression, and increased the density of BKCa currents, while genistein significantly inhibited these effects caused by Ox-LDL. BKCa channels exerted a regulatory role in the proliferation of VSMCs in response to Ox-LDL. The inhibition of BKCa channels suppressed Ox-LDL-stimulated VSMC proliferation, while the activation of BKCa channels showed the opposite effect. Moreover, genistein suppressed the activity of BKCa, including protein expression and current density in a protein tyrosine kinase- (PTK-) dependent manner. Conclusion. This study demonstrated that genistein inhibited the Ox-LDL-mediated proliferation of VSMCs by blocking the cell cycle progression; the possible molecular mechanism may be related to PTK-dependent suppression of BKCa channels. Our results provided novel ideas for the application of genistein in the treatment of vascular diseases and proposed a unique insight into the antiproliferative molecular mechanism of genistein.

Cysteinyl Leukotriene D4 Induced Vascular Smooth Muscle Cell Proliferation: A Possible Role in Myointimal Hyperplasia

1996 ◽  
Vol 76 (01) ◽  
pp. 099-104 ◽  
Author(s):  
Ettore Porreca ◽  
Concetta Di Febbo ◽  
Anna Di Sciullo ◽  
Domenico Angelucci ◽  
Mimmo Nasuti ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Thymidine Incorporation ◽  
Balloon Catheter ◽  
Dependent Manner ◽  
In Vitro Proliferation ◽  
Leukotriene D4 ◽  
Cysteinyl Leukotrienes ◽  
Vsmc Proliferation ◽  
Dose Dependent

SummaryCysteinyl leukotrienes (i.e. LTC4, LTD4), produced by activated leukocytes or by transcellular metabolism may act at different levels on vascular smooth muscle cells (VSMC) during inflammatory processes or atherosclerosis. We studied the effect of LTC4, LTD4, and LTE4 on the in vitro proliferation of rat VSMC, measured by [3H]-thymidine incorporation and cell count. LTD4 had a stronger stimulatory effect on [3H]-thymidine incorporation than LTC4, whereas LTE4 was inactive. The effect of LTD4 on [3H]-thymidine incorporation was dose-dependent, with the maximal activity at 10−6 M. The stimulatory activity of LTD4 was inhibited in a dose-dependent manner by MK-571, a specific LTD4 receptor antagonist. In addition, MK-571 (1 mg/kg/day) given for at least 1 day after injury in a model of balloon catheter injury of rat carotid artery, provided effective inhibition of myointimal VSMC proliferation, with a 58% reduction of 5-bromo-2’-deoxyuridine (BrdU) uptake in the neointima and 69% reduction of neointimal thickening. Our data support the importance of inflammatory mechanisms in the pathogenesis of atherosclerosis and suggest a possible role for cysteinyl leukotrienes, specifically LTD4, in the control of VSMC proliferation.

The indazole derivative YD-3 inhibits thrombin-induced vascular smooth muscle cell proliferation and attenuates intimal thickening after balloon injury

2004 ◽  
Vol 92 (12) ◽  
pp. 1232-1239 ◽  
Author(s):  
Jih-Hwa Guh ◽  
Yi-Nan Liu ◽  
Ya-Ling Chang ◽  
Sheng-Chu Kuo ◽  
Fang-Yu Lee ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Developmental Potential ◽  
Vsmc Proliferation ◽  
Neointimal Thickness ◽  
Immunochemical Detection

SummaryProliferation of vascular smooth muscle cells (VSMCs) is postulated to be one of the key events in the pathogenesis of atherosclerosis and restenosis. We investigated whether YD-3, a lowmolecular weight, non-peptide compound, could modulate proliferation of VSMCs in vitro and restenosis after balloon angioplasty in vivo. We examined the effect of YD-3 on thrombininduced VSMC proliferation by [3H]thymidine incorporation assay. The data demonstrated that YD-3 inhibited VSMC proliferation in a concentration-dependent manner. To define the mechanisms of YD-3 action, we found that YD-3 showed a profound inhibition on thrombin-induced Ras and ERK1/2 activities by using Western blotting analysis. Furthermore, oral administration of YD-3 exhibited a marked reduction in neointimal thickness using the carotid injury model in rats. Using immunochemical detection, our experiments also revealed that YD-3 significantly suppressed expression of the PAR-1 receptor, and markedly inhibited PAR-1-activating peptide (SFLLRN)-induced VSMC proliferation in a concentration-dependent manner. These results suggest that YD-3 inhibits thrombin-induced VSMC growth via the Rasand ERK1/2-mediated signaling pathway. Moreover, YD-3 also shows a developmental potential in the treatment of atherosclerosis and restenosis after vascular injury.

scholarly journals S-Propargyl-Cysteine Attenuates Diabetic Cardiomyopathy in db/db Mice Through Activation of Cardiac Insulin Receptor Signaling

2021 ◽  
Vol 8 ◽  
Author(s):  
Ye Li ◽  
Kui-Fang Xie ◽  
Ya-Hong Chang ◽  
Cheng Wang ◽  
Ying Chen ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Diabetic Cardiomyopathy ◽  
Glucose Transporter ◽  
Glycogen Synthase ◽  
Systolic Dysfunction ◽  
Fasting Blood Glucose ◽  
Functional Improvement ◽  
Dependent Manner ◽  
Receptor Signaling ◽  
Insulin Receptor Signaling

Background: Endogenous hydrogen sulfide (H2S) is emerging as a key signal molecule in the development of diabetic cardiomyopathy. The aim of this study was to explore the effect and underlying mechanism of S-propargyl-cysteine (SPRC), a novel modulator of endogenous H2S, on diabetic cardiomyopathy in db/db diabetic mice.Methods and Results: Vehicle or SPRC were orally administered to 8-month-old male db/db mice and their wild type littermate for 12 weeks. SPRC treatment ameliorated myocardial hypertrophy, fibrosis, and cardiac systolic dysfunction assessed by histopathological examinations and echocardiography. The functional improvement by SPRC was accompanied by a reduction in myocardial lipid accumulation and ameliorated plasma lipid profiles. SPRC treatment improved glucose tolerance in db/db mice, with fasting blood glucose and peripheral insulin resistance remaining unchanged. Furthermore, insulin receptor signaling involving the phosphorylation of protein kinase B (Akt/PKB) and glycogen synthase kinase 3β (GSK3β) were elevated and activated by SPRC treatment. Primary neonatal mice cardiomyocytes were cultured to explore the mechanisms of SPRC on diabetic cardiomyopathy in vitro. Consistent with the results in vivo, SPRC not only up-regulated insulin receptor signaling pathway in cardiomyocytes in dose-dependent manner in the basal state, but also relieved the suppression of insulin receptor signaling induced by high concentrations of glucose and insulin. Furthermore, SPRC also enhanced the expression of glucose transporter 4 (GLUT4) and 3H glucose uptake in cardiomyocytes.Conclusions: In this study, we found a novel beneficial effect of SPRC on diabetic cardiomyopathy, which was associated with activation of insulin receptor signaling. SPRC may be a promising medication for diabetic cardiomyopathy in type 2 diabetes mellitus patients.

scholarly journals Nitro-linoleic acid inhibits vascular smooth muscle cell proliferation via the Keap1/Nrf2 signaling pathway

2007 ◽  
Vol 293 (1) ◽  
pp. H770-H776 ◽  
Author(s):  
Luis Villacorta ◽  
Jifeng Zhang ◽  
Minerva T. Garcia-Barrio ◽  
Xi-lin Chen ◽  
Bruce A. Freeman ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Linoleic Acid ◽  
Vascular Smooth Muscle ◽  
Signaling Pathway ◽  
Related Factor ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Vsmc Proliferation ◽  
Nrf2 Signaling Pathway

Nitroalkenes, the nitration products of unsaturated fatty acids formed via NO-dependent oxidative reactions, have been demonstrated to exert strong biological actions in endothelial cells and monocytes/macrophages; however, little is known about their effects on vascular smooth muscle cells (VSMCs). The present study examined the role of nitro-linoleic acid (LNO2) in the regulation of VSMC proliferation. We observed that LNO2 inhibited VSMC proliferation in a dose-dependent manner. In addition, LNO2 induced growth arrest of VSMCs in the G1/S phase of the cell cycle with an upregulation of the cyclin-dependent kinase inhibitor p27kip1. Furthermore, LNO2 triggered nuclear factor-erythroid 2-related factor 2 (Nrf2) nuclear translocation and activation of the antioxidant-responsive element-driven transcriptional activity via impairing Kelch-like ECH-associating protein 1 (Keap1)-mediated negative control of Nrf2 activity in VSMCs. LNO2 upregulated the expression of Nrf2 protein levels, but not mRNA levels, in VSMCs. A forced activation of Nrf2 led to an upregulation of p27kip1 and growth inhibition of VSMCs. In contrast, knock down of Nrf2 using an Nrf2 siRNA approach reversed the LNO2-induced upregulation of p27kip1 and inhibition of cellular proliferation in VSMCs. These studies provide the first evidence that nitroalkene LNO2 inhibits VSMC proliferation through activation of the Keap1/Nrf2 signaling pathway, suggesting an important role of nitroalkenes in vascular biology.

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