Myocardin regulates vascular smooth muscle cell inflammatory activation and disease

Matthew Ackers-Johnson, Amarnath Talasila, Andrew P. Sage, Xiaochun Long, Ilze Bot, Nicholas W. Morrell, Martin R. Bennett, Joseph M. Miano, Sanjay Sinha

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

Objective - Atherosclerosis, the cause of 50% of deaths in westernized societies, is widely regarded as a chronic vascular inflammatory disease. Vascular smooth muscle cell (VSMC) inflammatory activation in response to local proinflammatory stimuli contributes to disease progression and is a pervasive feature in developing atherosclerotic plaques. Therefore, it is of considerable therapeutic importance to identify mechanisms that regulate the VSMC inflammatory response. Approach and Results - We report that myocardin, a powerful myogenic transcriptional coactivator, negatively regulates VSMC inflammatory activation and vascular disease. Myocardin levels are reduced during atherosclerosis, in association with phenotypic switching of smooth muscle cells. Myocardin deficiency accelerates atherogenesis in hypercholesterolemic apolipoprotein E-/- mice. Conversely, increased myocardin expression potently abrogates the induction of an array of inflammatory cytokines, chemokines, and adhesion molecules in VSMCs. Expression of myocardin in VSMCs reduces lipid uptake, macrophage interaction, chemotaxis, and macrophage-endothelial tethering in vitro, and attenuates monocyte accumulation within developing lesions in vivo. These results demonstrate that endogenous levels of myocardin are a critical regulator of vessel inflammation. Conclusions - We propose myocardin as a guardian of the contractile, noninflammatory VSMC phenotype, with loss of myocardin representing a critical permissive step in the process of phenotypic transition and inflammatory activation, at the onset of vascular disease.

Original languageEnglish (US)
Pages (from-to)817-828
Number of pages12
JournalArteriosclerosis, thrombosis, and vascular biology
Volume35
Issue number4
DOIs
StatePublished - Apr 27 2015
Externally publishedYes

Keywords

  • atherosclerosis
  • inflammation
  • myocardin
  • smooth muscle

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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