Salusin-? Promotes Vascular Calcification via Nicotinamide Adenine Dinucleotide Phosphate/Reactive Oxygen Species-Mediated Klotho Downregulation.

ABSTRACT: Aims: Vascular calcification (VC) is a hallmark feature of cardiovascular disease and a significant risk factor for morbidity and mortality. Salusin-? exerts cardiovascular regulating effects in hypertension, atherosclerosis, and diabetes. The present study was designed to examine the roles of salusin-? in the progression of VC and its downstream signaling mechanisms. Results: Salusin-? expression in both the aortas of VC rats induced by vitamin D3 and nicotine and vascular smooth muscle cells (VSMCs) incubated with calcifying media was increased. Salusin-? knockdown remarkably reduced VC, whereas overexpression of salusin-? exacerbated VC both in vitro and in vivo. Overexpression of salusin-? promoted the VSMC osteochondrogenic transition, decreased Klotho protein levels, enhanced Ras-related C3 botulinum toxin substrate 1 (Rac1) activity and the translocation of p47phox to the membrane, increased the expression of nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidase subunits and the production of reactive oxygen species (ROS) with or without calcifying media; however, salusin-? deficiency played the opposite roles. The calcification and downregulated Klotho protein levels induced by salusin-? were restored by ROS scavenger N-acetyl-l-cysteine, diphenyleneiodonium chloride [an inhibitor of flavin-containing enzyme, including NAD(P)H oxidase], or gene knockdown of NAD(P)H oxidase (NOX)-2, p22phox, or p47phox but were not affected by NOX-1 and NOX-4 knockdown. Klotho knockdown attenuated the protective effect of salusin-? deficiency on VSMC calcification. By contrast, exogenous Klotho ameliorated the development of VC and ROS generation induced by salusin-? overexpression. Innovation: Salusin-? is a critical modulator in VC. Conclusion: Salusin-? regulates VC through activation of NAD(P)H/ROS-mediated Klotho downregulation, suggesting that salusin-? may be a novel target for treatment of VC.

SUBMITTER: Sun H 

PROVIDER: S-EPMC6998059 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature