ADAR1‐mediated RNA editing, a novel mechanism controlling phenotypic modulation of vascular smooth muscle cells

Abstract

Vascular smooth muscle cell (VSMC) phenotypic modulation plays a critical role in the development and progression of several proliferative cardiovascular diseases such as atherosclerosis, hypertension, restenosis after angioplasty or bypass, diabetic vascular complications, and transplantation arteriopathy. A hallmark feature of the phenotypic modulation is the down‐regulation of SMC contractile genes. Platelet‐derived growth factor‐BB (PDGF‐BB), a well‐known stimulator of SMC phenotypic modulation, down‐regulates SMC gene expression via posttranscriptional regulation of the related genes. The post‐transcriptional mechanisms involved in SMC phenotypic gene expression, however, remain largely unknown. We found that the down‐regulation of SMC contractile genes is caused by abnormal RNA splicing of their precursor mRNAs (pre‐mRNAs). This abnormal pre‐mRNA editing is facilitated by adenosine deaminase acting on RNA (ADAR), which converts adenosines to inosines (A→I editing). PDGF‐BB induces ADAR1 while down‐regulating the expression of SMC myosin heavy chain (SMMHC) and calponin (CNN). Knockdown of ADAR1 by shRNA restores PDGF‐BB‐blocked SMMHC and CNN expression, demonstrating that ADAR1 plays an essential role in SMC phenotype modulation. In vivo animal studies show that SMMHC and CNN pre‐mRNA is accumulated while their mature mRNA is decreased in balloon‐injured rat carotid arteries. Moreover, ADAR1 is highly induced in media layer SMCs initially, and neointima SMCs subsequently following the injury. Our study suggests that ADAR1‐mediated RNA splicing may also play an important role in VSMC phenotypic modulation and vascular remodeling in vivo.