Akt1 isoform modulates phenotypic conversion of vascular smooth muscle cells

Abstract

In this study, we investigated the role of Akt1 isoform in phenotypic change of vascular smooth muscle cells (VSMCs) and neointima formation. Laminin-induced conversion of synthetic VSMCs into contractile VSMCs was measured by expression of marker proteins for contractile VSMCs and collagen gel contraction assay. Culture of synthetic VSMCs on laminin-coated plates induced expression of marker proteins for contractile VSMCs and showed contraction in response to angiotensin II (AngII) stimulation. Silencing integrin-linked kinase attenuated activation of Akt and blocked phenotypic conversion of VSMCs resulting in the loss of AngII-dependent contraction. Laminin-induced phenotypic conversion of VSMCs was abrogated by phosphatidylinositol 3-kinase inhibitor or in cells silencing Akt1 but not Akt2. Proliferation of contractile VSMCs on laminin-coated plate was enhanced in cells silencing Akt1 whereas silencing Akt2 did not affect. Promoter activity of myocardin and SM22α was enhanced in contractile phenotype and overexpression of myocardin stimulated promoter activity of SM22α in synthetic phenotype. Promoter activity of myocardin and SM22α was reduced in cells silencing Akt1 and promoter activity of SM22α was restored by overexpression of myocardin in cells silencing Akt1. However, silencing of Akt2 affected neither promoter activity of myocardin nor SM22α. Finally, neointima formation in carotid artery ligation and high fat-diet-induced atherosclerosis was facilitated in mice lacking Akt1. This study demonstrates that Akt1 isoform stimulates laminin-induced phenotypic conversion of synthetic VSMCs by regulating the expression of myocardin. VSMCs become susceptible to shifting from contractile to synthetic phenotype by the loss of Akt1 in pathological conditions.

Leukotriene-C4 Synthase, a Critical Enzyme in the Activation of Store-independent Orai1/Orai3 Channels, Is Required for Neointimal Hyperplasia

“…5 Furthermore, it was shown that the downstream target of Akt2 at the transcriptional level is GATA-6, which drives the expression of VSMC differentiation genes. 6 A recent study showed that neointima formation in carotid artery ligation and high fat dietinduced atherosclerosis was facilitated in mice lacking Akt1 (50). Moreover, down-regulation of the Akt1 isoform in epithelial cells promoted enhanced cell migration and substantial neomorphic effects typical of the epithelial to mesenchymal transition (51).…”

Essential role of krüppel-like factor 5 during tumor necrosis factor α-induced phenotypic conversion of vascular smooth muscle cells

“…VSMCs were isolated from 4-week-old SpragueeDawley rats as described previously [14]. Briefly, rats were euthanized via intraperitoneal injection of sodium pentobarbital (60 mg/kg) and perfused with PBS for 5 min.…”

Deletion of Methionine Sulfoxide Reductase A Does Not Affect Atherothrombosis but Promotes Neointimal Hyperplasia and Extracellular Signal-Regulated Kinase 1/2 Signaling

“…Numerous studies have mechanistically implicated Akt in VSMC proliferation. 37-40 Thus, we tested the hypothesis that Akt-dependent signaling is elevated in MsrA −/− VSMC. Unexpectedly, we did not detect a difference in PTEN expression or Akt signaling following deletion of MsrA.…”