Hyperinsulinemia-induced vascular smooth muscle cell (VSMC) migration and proliferation is mediated by converging mechanisms of mitochondrial dysfunction and oxidative stress

Abhijit, Shiny; Regin, Bhaskaran; Narayanasamy, Abirami; Chakroborty, Anand; Manickam, Nagaraj; Dixit, Madhulika; Mohan, Viswanathan; Balasubramanyam, Muthuswamy

doi:10.1007/s11010-012-1478-5

Cited by 39 publications

(25 citation statements)

References 49 publications

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“…These observations are consistent with previous studies showing that VSMC in diabetic models exhibit sustained activation of AKT after chronic hyperglycemia 43 , although other studies reported blunted AKT activation in diabetic cardiomyocytes and myotubes 44,45 . Apparently, AKT may be differentially regulated depending upon cell types, cellular environment and disease status.…”

Section: Discussionsupporting

confidence: 93%

Activation of AKT by O-Linked N-Acetylglucosamine Induces Vascular Calcification in Diabetes Mellitus

Heath

Sun

Yuan

et al. 2014

Circulation Research

127

108

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Rationale Vascular calcification is a serious cardiovascular complication that contributes to the increased morbidity and mortality of patients with diabetes. Hyperglycemia, a hallmark of diabetes, is associated with increased vascular calcification as well as increased modification of proteins by O-linked N-acetylglucosamine (O-GlcNAcylation). Objective We sought to determine the role of protein O-GlcNAcylation in regulating vascular calcification and the underlying mechanisms. Methods and Results Low-dose streptozotocin-induced diabetic mice exhibited increased aortic O-GlcNAcylation and vascular calcification, which also was associated with impaired aortic compliance in mice. Elevation of O-GlcNAcylation by administration of Thiamet-G, a potent inhibitor for O-GlcNAcase (OGA) that removes O-GlcNAcylation, further accelerated vascular calcification and worsened aortic compliance of diabetic mice in vivo. Increased O-GlcNAcylation, either by Thiamet-G or OGA knockdown, promoted calcification of primary mouse vascular smooth muscle cells (VSMC). Increased O-GlcNAcylation in diabetic arteries or in the OGA knockdown VSMC upregulated expression of the osteogenic transcription factor Runx2 and enhanced activation of AKT. O-GlcNAcylation of AKT at two new O-sites, T430 and T479, promoted AKT phosphorylation, which in turn enhanced VSMC calcification. Site-directed mutation of AKT at T430 and T479 decreased O-GlcNAcylation, inhibited phosphorylation of AKT at S473 and binding of mTOR complex 2 to AKT, and subsequently blocked Runx2 transactivity and VSMC calcification. Conclusions O-GlcNAcylation of AKT at two new sites enhanced AKT phosphorylation and activation, thus promoting vascular calcification. Our studies have identified a novel causative effect of O-GlcNAcylation in regulating vascular calcification in diabetes and uncovered a key molecular mechanism underlying O-GlcNAcylation-mediated activation of AKT.

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Section: Discussionsupporting

confidence: 93%

Activation of AKT by O-Linked N-Acetylglucosamine Induces Vascular Calcification in Diabetes Mellitus

Heath

Sun

Yuan

et al. 2014

Circulation Research

127

108

View full text Add to dashboard Cite

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“…Furthermore, in bovine aortic VSMCs 10 nmol/L insulin moderately stimulated migration mainly through the MAPK pathway, whereas insulin maintained VSMC quiescence and differentiation via PI3K-dependent signaling [34]. In others studies, a high dose of insulin (100 nmol/L) was found to induce migration and proliferation of both human and rat VSMCs [35, 36]. Nevertheless, this supraphysiological concentration of insulin can stimulate IGF-IR, which is known to mediate VSMC migration [4].…”

Section: Discussionmentioning

confidence: 99%

Expression of insulin receptor (IR) A and B isoforms, IGF-IR, and IR/IGF-IR hybrid receptors in vascular smooth muscle cells and their role in cell migration in atherosclerosis

Beneit

Fernandez-Garcia

Martı́n-Ventura

et al. 2016

Cardiovasc Diabetol

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BackgroundAbnormal proliferation and migration of vascular smooth muscle cells (VSMCs) is a major contributor to the development of atherosclerotic process. In a previous work, we demonstrated that the insulin receptor isoform A (IRA) and its association with the insulin-like growth factor-I receptor (IGF-IR) confer a proliferative advantage to VSMCs. However, the role of IR and IGF-IR in VSMC migration remains poorly understood.MethodsWound healing assays were performed in VSMCs bearing IR (IRLoxP+/+ VSMCs), or not (IR−/− VSMCs), expressing IRA (IRA VSMCs) or expressing IRB (IRB VSMCs). To study the role of IR isoforms and IGF-IR in experimental atherosclerosis, we used ApoE−/− mice at 8, 12, 18 and 24 weeks of age. Finally, we analyzed the mRNA expression of total IR, IRB isoform, IGF-IR and IGFs by qRT-PCR in the medial layer of human aortas.ResultsIGF-I strongly induced migration of the four cell lines through IGF-IR. In contrast, insulin and IGF-II only caused a significant increase of IRA VSMC migration which might be favored by the formation of IRA/IGF-IR receptors. Additionally, a specific IGF-IR inhibitor, picropodophyllin, completely abolished insulin- and IGF-II-induced migration in IRB, but not in IRA VSMCs. A significant increase of IRA and IGF-IR, and VSMC migration were observed in fibrous plaques from 24-week-old ApoE−/− mice. Finally, we observed a marked increase of IGF-IR, IGF-I and IGF-II in media from fatty streaks as compared with both healthy aortas and fibrolipidic lesions, favoring the ability of medial VSMCs to migrate into the intima.ConclusionsOur data suggest that overexpression of IGF-IR or IRA isoform, as homodimers or as part of IRA/IGF-IR hybrid receptors, confers a stronger migratory capability to VSMCs as might occur in early stages of atherosclerotic process.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-016-0477-3) contains supplementary material, which is available to authorized users.

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“…Insulin resistance and hyperinsulinemia are important risk factors for cardiovascular disease due, in part, to the VSM proliferative and pro-atherogenic actions of insulin [3,5,24,25]. Therefore, reducing the stimulatory effect of insulin on VSMC proliferation and migration may provide new insights in the prevention of atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

Dopamine D4 receptors inhibit proliferation and migration of vascular smooth muscle cells induced by insulin via down-regulation of insulin receptor expression

Wang

Han

et al. 2014

Cardiovasc Diabetol

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Vascular smooth muscle cells (VSMCs) proliferation and migration, which are central in the development of vascular diseases, are regulated by numerous hormones and humoral factors. Activation of the insulin receptor stimulates VSMCs proliferation while dopamine receptors, via D1 and D3 receptors, inhibit the stimulatory effects of norepinephrine on VSMCs proliferation. We hypothesize that activation of the D4 dopamine receptor may also inhibit the proliferation and migration of VSMCs, therefore, inhibit atherosclerosis. Our current study found that insulin increased the proliferation and migration of A10 cells, an effect that was reduced in the presence of a D4 receptor agonist, PD168077. The negative effect of the D4 receptor on insulin’s action may be via decreasing insulin receptor expression, because activation of the D4 receptor inhibited insulin receptor protein and mRNA expressions, indicating that the regulation occured at the transcriptional or post-transcriptional levels. To determine whether or not the inhibition of D4 receptor on insulin-mediated proliferation and migration of VSMCs has physiological significance, hyper-insulinemic Sprague–Dawley rats with balloon-injured carotid artery were treated with a D4 agonist, PD168077, (6 mg/kg/d) for 14 days. We found that PD168077 significantly inhibited neointimal formation by inhibition of VSMC proliferation. This study suggests that activation of the D4 receptor suppresses the proliferation and migration of VSMCs, therefore, inhibit atherosclerosis. The D4 receptor may be a potential therapeutic target to reduce the effects of insulin on artery remodeling.

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Hyperinsulinemia-induced vascular smooth muscle cell (VSMC) migration and proliferation is mediated by converging mechanisms of mitochondrial dysfunction and oxidative stress

Cited by 39 publications

References 49 publications

Activation of AKT by O-Linked N-Acetylglucosamine Induces Vascular Calcification in Diabetes Mellitus

Activation of AKT by O-Linked N-Acetylglucosamine Induces Vascular Calcification in Diabetes Mellitus

Expression of insulin receptor (IR) A and B isoforms, IGF-IR, and IR/IGF-IR hybrid receptors in vascular smooth muscle cells and their role in cell migration in atherosclerosis

Dopamine D4 receptors inhibit proliferation and migration of vascular smooth muscle cells induced by insulin via down-regulation of insulin receptor expression

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