Mechanistic study of ARHGAP27 promoting the progression of aortic dissection by regulating the RhoA/ROCK/YAP pathway.

BACKGROUND

Aortic dissection (AD) is a life-threatening cardiovascular disease. ARHGAP27 can regulate cytoskeleton and cellular functions, which may be related to the phenotypic switching of vascular smooth muscle cells (VSMCs) in AD. However, the role of ARHGAP27 in AD has not been reported yet.

METHODS

The AD-related data sets were downloaded from GEO database to screen differential genes. HE and IHC staining was used to detect the pathological changes and the expression level of ARHGAP27 in AD tissue. AD cell models were constructed in vitro by inducing HAVSMCs with PDGF-BB to evaluate the effects of ARHGAP27 overexpression or knockdown on cell survival, migration, invasion and phenotypic switching. Rescue experiments were performed using the ROCK activator LPA to test pathway specificity.

RESULTS

ARHGAP27 was significantly upregulated in the dataset and the tissue. In vitro experiments have shown that overexpression of ARHGAP27 can further promote the survival, migration and invasion of VSMCs, and the expression of synthetic phenotypic proteins MMP2 and MMP9, and inhibit the expression of contraction phenotypes α-SMA and SM22α. Knockdown of ARHGAP27-2 can obtain the opposite result. In terms of mechanism, PDGF-BB down-regulates the expression levels of RhoA, ROCK1/2, and up-regulates the phosphorylation levels of YAP in VSMCs. Overexpression of ARHGAP27 further enhances the effect of PDGF-BB, while knockdown of ARHGAP27-1 and ARHGAP27-2 inhibits the effect of PDGF-BB. Treatment with LPA would reverse the effects produced by ARHGAP27 overexpression.

CONCLUSION

ARHGAP27 is upregulated in AD and accelerates its pathological progression by regulating the RhoA/ROCK/YAP pathway.