Cholesterol loading reprograms the microRNA-143/145-Myocardin axis to convert aortic smooth muscle cells to a dysfunctional macrophage-like phenotype

Yuliya Vengrenyuk, Hitoo Nishi, Xiaochun Long, Mireille Ouimet, Nazir Savji, Fernando O. Martinez, Courtney P. Cassella, Kathryn J. Moore, Stephen A. Ramsey, Joseph M. Miano, Edward A. Fisher

Research output: Contribution to journalArticle

116 Scopus citations

Abstract

Objective-We previously showed that cholesterol loading in vitro converts mouse aortic vascular smooth muscle cells (VSMC) from a contractile state to one resembling macrophages. In human and mouse atherosclerotic plaques, it has become appreciated that ?40% of cells classified as macrophages by histological markers may be of VSMC origin. Therefore, we sought to gain insight into the molecular regulation of this clinically relevant process. Approach and Results-VSMC of mouse (or human) origin were incubated with cyclodextrin-cholesterol complexes for 72 hours, at which time the expression at the protein and mRNA levels of contractile-related proteins was reduced and of macrophage markers increased. Concurrent was downregulation of miR-143/145, which positively regulate the master VSMC differentiation transcription factor myocardin. Mechanisms were further probed in mouse VSMC. Maintaining the expression of myocardin or miR-143/145 prevented and reversed phenotypic changes caused by cholesterol loading. Reversal was also seen when cholesterol efflux was stimulated after loading. Notably, despite expression of macrophage markers, bioinformatic analyses showed that cholesterol-loaded cells remained closer to the VSMC state, consistent with impairment in classical macrophage functions of phagocytosis and efferocytosis. In apoE-deficient atherosclerotic plaques, cells positive for VSMC and macrophage markers were found lining the cholesterol-rich necrotic core. Conclusions-Cholesterol loading of VSMC converts them to a macrophage-appearing state by downregulating the miR-143/145-myocardin axis. Although these cells would be classified by immunohistochemistry as macrophages in human and mouse plaques, their transcriptome and functional properties imply that their contributions to atherogenesis would not be those of classical macrophages.

Original languageEnglish (US)
Pages (from-to)535-546
Number of pages12
JournalArteriosclerosis, thrombosis, and vascular biology
Volume35
Issue number3
DOIs
StatePublished - Mar 2015

Keywords

  • Atherosclerosis
  • Atherosclerotic
  • Cholesterol
  • Macrophages
  • Plaque

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Fingerprint Dive into the research topics of 'Cholesterol loading reprograms the microRNA-143/145-Myocardin axis to convert aortic smooth muscle cells to a dysfunctional macrophage-like phenotype'. Together they form a unique fingerprint.

  • Cite this