伸展負荷によるラット血管平滑筋細胞死に対してNR4A1はp38経路を介して防御的に作用する。

抄録

Cyclic mechanical stretch (CMS) causes vascular smooth muscle cell (VSMC) proliferation, cell death, and migration, resulting in vascular remodeling and subsequent vascular failure during hypertension. However, the effect of CMS on gene induction in cardiovascular disease remains to be determined. Previously, we demonstrated that CMS caused cell death in rat aorta smooth muscle cells (RASMCs) in a JNK- and p38-dependent manner. To investigate the role of CMS in initiating cell death signaling and MAPK-related events, we used cDNA microarrays to examine the transcript profiles of CMS-induced RASMCs and discovered that the transcripts of 29 differentially expressed genes, including NR4A1, were significantly increased in response to CMS. Quantitative polymerase chain reaction (qPCR) analysis demonstrated that this increase of NR4A1 was p38-dependent. Moreover, we studied the function of NR4A1 in the early response of RASMCs to CMS. An inhibitor (CDIM8) of NR4A1 strongly increased CMS-induced cell death in vitro. We also examined NR4A1 expression in arteries using an abdominal aortic constriction (AAC) mouse model. We discovered that hypertension enhanced NR4A1 expression at both the mRNA and protein levels in arteries treated to AAC compared to sham-operated arteries using qPCR analysis and immunofluorescence staining. Taken together, our data provide the first evidence that NR4A1 protects RASMCs from CMS-stimulated cell death via the p38 signaling pathway.