Cyclosporine Up-Regulates Krüppel-Like Factor-4 (KLF4) in Vascular Smooth Muscle Cells and Drives Phenotypic Modulation In Vivo

Garvey, Sean M.; Sinden, Daniel S.; Bortz, Pamela D. Schoppee; Wamhoff, Brian R.

doi:10.1124/jpet.109.163949

Cited by 44 publications

(29 citation statements)

References 47 publications

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“…Cyclosporine, which induces KLF-4 expression, also induces smooth muscle cell dedifferentiation (37). In contrast, myocardin overexpression promotes VSMC differentiation and increases the expression of other VSMC marker proteins (38).…”

Section: Irs-1 Prevents Vsmc Dedifferentiationmentioning

confidence: 99%

Down-regulation of Insulin Receptor Substrate 1 during Hyperglycemia Induces Vascular Smooth Muscle Cell Dedifferentiation

Wai

White

et al. 2017

Journal of Biological Chemistry

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Edited by Jeffrey E. PessinDiabetes is a major risk factor for the development of atherosclerosis, but the mechanism by which hyperglycemia accelerates lesion development is not well defined. Insulin and insulinlike growth factor I (IGF-I) signal through the scaffold protein insulin receptor substrate 1 (IRS-1). In diabetes, IRS-1 is downregulated, and cells become resistant to insulin. Under these conditions, the IGF-I receptor signals through an alternate scaffold protein, SHPS-1, resulting in pathophysiologic stimulation of vascular smooth muscle cell (VSMC) migration and proliferation. These studies were undertaken to determine whether IRS-1 is functioning constitutively to maintain VSMCs in their differentiated state and, thereby, inhibit aberrant signaling. Here we show that deletion of IRS-1 expression in VSMCs in nondiabetic mice results in dedifferentiation, SHPS-1 activation, and aberrant signaling and that these changes parallel those that occur in response to hyperglycemia. The mice showed enhanced sensitivity to IGF-I stimulation of VSMC proliferation and a hyperproliferative response to vascular injury. KLF4, a transcription factor that induces VSMC dedifferentiation, was up-regulated in IRS-1 ؊/؊ mice, and the differentiation inducer myocardin was undetectable. Importantly, these changes were replicated in wild-type mice during hyperglycemia. These findings illuminate a new function of IRS-1: that of maintaining cells in their normal, differentiatedstate.BecauseIRS-1isdown-regulatedinstatesofinsulinresistance that occur in response to metabolic stresses such as obesity and cytokine stimulation, the findings provide a mechanism for understanding how patients with metabolic stress and/or diabetes are predisposed to developing vascular complications.Diabetes is a major predisposing factor for the development of atherosclerosis. The diabetes control complications trial showed that patients with type 1 diabetes who maintained a hemoglobin A-1 C value 1.2% lower than control subjects for 7 years had a significantly reduced rate of vascular disease events during the 20-year follow-up period (1). Similarly the United Kingdom prospective trial demonstrated a significant benefit of lowering glucose in type 2 diabetics on cardiovascular risk (2). Despite intense analysis, the molecular mechanism by which glucose lowering results in a clinical benefit has remained poorly defined. Insulin and insulin-like growth factor I (IGF-I) 2 signal through a scaffold protein termed insulin receptor substrate 1 (IRS-1) (3). The insulin and IGF-I receptor tyrosine kinases directly phosphorylate IRS-1, and these phosphotyrosines recruit the p85 subunit of PI3K and Grb-2, thereby activating the PI3K and MAPK pathways (4). In differentiated cells, these IRS-1-linked signaling cascades promote glucose influx; glycogen, lipid, and protein synthesis; as well as changes in gene expression (5). Under normal physiologic conditions, both insulin and IGF-I stimulate differentiated cell functions through IRS-1 activation (6 -7). In re...

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Section: Irs-1 Prevents Vsmc Dedifferentiationmentioning

confidence: 99%

Down-regulation of Insulin Receptor Substrate 1 during Hyperglycemia Induces Vascular Smooth Muscle Cell Dedifferentiation

Wai

White

et al. 2017

Journal of Biological Chemistry

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“…Further, miR-145 represses Kruppel-like factor 4 (Klf4), which was shown to be involved in multiple events including neointimal proliferation. Klf4 plays a key role in regulating the VSMC phenotype because it facilitates VSMC migration and downregulates VSMC differentiation marker genes (9).…”

Section: Introductionmentioning

confidence: 99%

Angiotensin II Downregulates MicroRNA-145 to Regulate Kruppel-like Factor 4 and Myocardin Expression in Human Coronary Arterial Smooth Muscle Cells under High Glucose Conditions

Shyu

Cheng²,

Wang³

2015

Mol Med

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MicroRNA (miR)-145 is the most abundant miR in vascular smooth muscle cells (VSMCs). However, the effect of hyperglycemia on the regulation of miR-145 is unknown. We hypothesized that the hyperglycemic condition activates a proinflammatory response that mediates the expression of miR-145 in VSMCs. We investigated whether miR-145 serves as a critical regulator to regulate the downstream proliferation factors (including Kruppel-like factor 4 [Klf4] and myocardin) in VSMCs under hyperglycemic conditions. Human coronary artery smooth muscle cells (HCASMCs) were cultured under high glucose conditions. Sustained high glucose at 25 mmol/L significantly decreased the expression of miR-145 in HCASMCs. High glucose significantly increased angiotensin II (Ang II) secretion from HCASMCs and Ang II suppressed miR-145 expression in HCASMCs. Ang II repression of miR145 expression resulted in increased Klf4 and decreased myocardin expression under conditions of high glucose. Overexpression of miR-145 significantly decreased Klf4 and increased myocardin expression and inhibited HCASMC proliferation and migration induced by a high glucose state. Balloon injury of the carotid artery in diabetic rats was performed to investigate miR-145, Klf and myocardin expression. The expression of miR-145 was maximally increased at 7 d after carotid injury and gradually declined thereafter. Overexpression of miR-145 and treatment with valsartan reversed Klf4 and myocardin protein expression induced by balloon injury and improved vascular injury. In conclusion, our study reveals that Ang II downregulates miR-145 to regulate Klf4 and myocardin expression in HCASMCs under high glucose conditions. Ang II plays a critical role in the regulation of miR-145 under hyperglycemic conditions.

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“…43 Klf4 plays a key role in regulating VSMC phenotype because it antagonizes proliferation, facilitates migration, and downregulates VSMC differentiation marker genes. 44 In another study, versican was identified as a new target for miR-143. 45 Versican is a chondroitin sulfate proteoglycan of the extracellular matrix, produced by synthetic VSMCs, and promotes VSMC migration and proliferation.…”

Section: Mir-143/145 Regulation Of Vsmc Proliferation and Differentiamentioning

confidence: 99%

miR-143 and miR-145

Rangrez

Massy²,

Meuth³

et al. 2011

Circ Cardiovasc Genet

184

100

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Cyclosporine Up-Regulates Krüppel-Like Factor-4 (KLF4) in Vascular Smooth Muscle Cells and Drives Phenotypic Modulation In Vivo

Cited by 44 publications

References 47 publications

Down-regulation of Insulin Receptor Substrate 1 during Hyperglycemia Induces Vascular Smooth Muscle Cell Dedifferentiation

Down-regulation of Insulin Receptor Substrate 1 during Hyperglycemia Induces Vascular Smooth Muscle Cell Dedifferentiation

Angiotensin II Downregulates MicroRNA-145 to Regulate Kruppel-like Factor 4 and Myocardin Expression in Human Coronary Arterial Smooth Muscle Cells under High Glucose Conditions

miR-143 and miR-145

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