MG53 Protein Protects Aortic Valve Interstitial Cells from Membrane Injury and Fibrocalcific Remodeling

Abstract

The aortic valve of the heart experiences constant mechanical stress under physiological conditions. Maladaptive valve injury responses contribute to the development of valvular heart disease (VHD). Here we test the hypothesis that MG53, an essential cell membrane repair protein, can protect valvular cells from injury and fibrocalcific remodeling processes associated with VHD. We found that MG53 is expressed in pig and human patient aortic valves and observed aortic valve disease in aged Mg53−/− mice. Aortic valves of Mg53−/− mice showed compromised cell membrane integrity. In vitro studies demonstrated that recombinant human MG53 (rhMG53) protein protects primary valve interstitial cells (VICs) from mechanical injury and that, in addition to mediating membrane repair, rhMG53 can enter VICs and suppress transforming growth factor‐b‐dependent activation of fibrocalcific signaling. Given the preserved contractile function of Mg53−/− mouse hearts under physiological conditions, the observation that aged Mg53−/− mice display hemodynamic and histological signs of aortic valve disease highlights a critical in vivo mechanism of MG53‐mediated valvular protection. Overall, our work revealed a dual function for MG53 in maintaining the integrity of the VICs and in controlling TGF‐β‐mediated fibrotic remodeling associated with VHD.Support or Funding InformationResearch Support: RO1 grants (HL069000 and AR070752) from NIH to J.M.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.