MG53-Mediated Protection in Heart Valve Biology

Utilizing both overexpression and extracellular application, we aim to target MG53, an essential cell membrane repair protein, to valvular cells for treatment of tissue injuries associated with valvular heart disease (VHD). Membrane repair is important to maintain normal cellular physiology, and disruption of this process can result in disease in a number of different tissues. With the four heart valves experiencing a tremendous amount of mechanical stress, we have utilized microelectrode needle penetration and glass bead damage assays to assess the ability of MG53 to protect valvular interstitial cells (VICs) from physical injury. Furthermore, we have begun in vitro and in vivo studies to investigate the ability of MG53 to protect against the biological and physiological changes associated with VHD. To date, we have observed MG53 expression in valvular tissue and MG53-mediated protection against membrane damage through both live cell imaging and lactate dehydrogenase (LDH) release. Ongoing experiments are further characterizing mechanisms of protection against valvular fibrosis and calcification and assessing the effects of MG53 in in vivo models of VHD. Specifically, we have found that, in addition to protecting against cell membrane injury, recombinant human MG53 (rhMG53) can enter VICs and suppress TGF-beta-dependent activation of Smad and MAPK signaling associated with fibrocalcific valvular remodeling. We anticipate that, once all of our aims are completed, our experiments will greatly contribute to the study of cell biology, regenerative medicine, and cardiovascular disease, the number one cause of death in the United States and worldwide.