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Salusin-β promotes vascular calcification via NAD(P)H/ROS mediated Klotho downregulation.

AIMS
Vascular calcification (VC) is a hallmark feature of cardiovascular disease and a significant risk factor for morbidity and mortality. Salusin-β exerts cardiovascular regulating effects in hypertension, atherosclerosis and diabetes. The present study was designed to examine the roles of salusin-β in the progression of VC and its downstream signaling mechanisms.


RESULTS
Salusin-β 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-β knockdown remarkably reduced VC, while overexpression of salusin-β exacerbated VC both in vitro and in vivo. Overexpression of salusin-β promoted the VSMC osteochondrogenic transition, decreased Klotho protein levels, enhanced Rac1 activity and the translocation of p47phox to the membrane, increased expression of NAD(P)H oxidase subunits and the production of reactive oxygen species (ROS) with or without calcifying media, however, salusin-β deficiency played the opposite roles. The calcification and downregulated Klotho protein levels induced by salusin-β were restored by ROS scavenger NAC, DPI (an inhibitor of flavin-containing enzyme, including NAD(P)H oxidase), or gene knockdown of NOX-2, p22phox or p47phox, but were not affected by NOX-1 and NOX-4 knockdown. Klotho knockdown attenuated the protective effect of salusin-β deficiency on VSMC calcification. By contrast, exogenous Klotho ameliorated the development of VC and ROS generation induced by salusin-β overexpression.


INNOVATION
Salusin-β is a critical modulator in vascular calcification.


CONCLUSION
Salusin-β regulates VC through activation of NAD(P)H/ROS mediated Klotho downregulation, suggesting that salusin-β may be a novel target for treatment of VC.