Salusin-β contributes to vascular remodeling associated with hypertension via promoting vascular smooth muscle cell proliferation and vascular fibrosis

Hai-Jian Sun; Tong-Yan Liu; Feng Zhang; Xiao-Qing Xiong; Jue-Jin Wang; Qi Chen; Yue-Hua Li; Yu-Ming Kang; Ye-Bo Zhou; Ying Han; Xing-Ya Gao; Guo-Qing Zhu

doi:10.1016/j.bbadis.2015.05.008

Salusin-β contributes to vascular remodeling associated with hypertension via promoting vascular smooth muscle cell proliferation and vascular fibrosis

Biochim Biophys Acta. 2015 Sep;1852(9):1709-18. doi: 10.1016/j.bbadis.2015.05.008. Epub 2015 May 19.

Authors

Affiliations

¹ Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
² Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
³ Department of Physiology and Pathophysiology, Cardiovascular Research Center, Xi'an Jiaotong University School of Medicine, Xi'an 710061, China.
⁴ Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu 210029, China. Electronic address: gqzhucn@njmu.edu.cn.

PMID: 26001930
DOI: 10.1016/j.bbadis.2015.05.008

Abstract

Vascular smooth muscle cell (VSMC) proliferation and vascular fibrosis are closely linked with hypertension and atherosclerosis. Salusin-β is a bioactive peptide involved in the pathogenesis of atherosclerosis. However, it is still largely undefined whether salusin-β is a potential candidate in the VSMC proliferation and vascular fibrosis. Experiments were carried out in human vascular smooth muscle cells (VSMCs) and in rats with intravenous injection of lentivirus expressing salusin-β. In vitro, salusin-β promoted VSMCs proliferation, which was attenuated by adenylate cyclase inhibitor SQ22536, PKA inhibitor Rp-cAMP, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor AG1478, ERK inhibitor U0126 or cAMP response element binding protein (CREB) inhibitor KG501. It promoted the phosphorylation of ERK1/2, CREB and EGFR, which were abolished by SQ22536 or Rp-cAMP. Furthermore, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor AG1478 diminished the salusin-β-evoked ERK1/2 and CREB phosphorylation. On the other hand, salusin-β increased collagen-I, collagen-III, fibronectin and connective tissue growth factor (CTGF) mRNA and phosphorylation of Smad2/3, which were prevented by ALK5 inhibitor A83-01. In vivo, salusin-β overexpression increased the media thickness, media/lumen ratio coupled with ERK1/2, CREB, EGFR and Smad2/3 phosphorylation, as well as the mRNA of collagen-I, collagen-III, fibronectin, transforming growth factor-β1 (TGF-β1) and CTGF in arteries. Moreover, salusin-β overexpression in rats caused severe hypertension. Intravenous injection of salusin-β dose-relatedly increased blood pressure, but excessive salusin-β decreased blood pressure and heart rate. These results indicate that salusin-β promotes VSMC proliferation via cAMP-PKA-EGFR-CREB/ERK pathway and vascular fibrosis via TGF-β1-Smad pathway. Increased salusin-β contributes to vascular remodeling and hypertension.

Keywords: Fibrosis; Hypertension; Proliferation; Salusin; Vascular remodeling.