The mammalian heart has a poor ability to regenerate heart muscle following myocardial infarction and dead cardiac muscle is replaced by scar tissue. Scar tissue is non-contractile, induces adverse cardiac remodeling and leads to dilatation of cardiac chambers, cardiomyocyte hypertrophy and development of heart failure. Despite optimal use of cardiovascular drugs, adverse remodeling following myocardial infarction contributes to 40% of all new case of heart failure. There thus exists an immense need to identify new targets for attenuating post infarct remodeling and development of heart failure. In this application, we identify GPNMB (Glycoprotein Non-Metastatic Melanoma Protein B) as a novel target for attenuating post infarct cardiac remodeling. We identified the protein using a systems genetics approach, in which a panel of inbred strains of mice were studied for heart failure traits in response to isoproterenol treatment. We demonstrate that GPNMB expression increases by an order of magnitude in infarcted murine hearts and regulates wound healing events in the heart early following injury. We show that macrophages that are recruited to the infarcted heart are the primary source of GPNMB expression. Using loss and gain of function approaches, we demonstrate that GPNMB activates cardiac fibroblasts and induces profound cardiomyocyte hypertrophy. In contrast, genetic deletion of GPNMB leads to attenuation of post infarct cardiac remodeling and is associated with better preservation of cardiac function. We also provide data that GPNMB plasma levels in humans is strongly associated with heart failure strengthening a causal relationship between GPNMB and the development of post infarct heart failure. Considering these observations, we hypothesize that GPNMB regulates (i) post infarct cardiac remodeling and (ii) inhibition of GPNMB will attenuate post infarct cardiac remodeling. We have assembled a multi-disciplinary team comprising expertise in cardiac physiology, genetics and extracellular matrix biology to interrogate the role and mechanisms of GPNMB in regulating post infarct cardiac remodeling. In the first aim, we will examine the role of GPNMB on cardiac remodeling with gain and loss of function approaches. In the second aim, we will identify mechanisms of GPNMB activation and use physico-chemical studies to determine the receptor to which GPNMB ligand binds and GPNMB domains critical for binding. In the third aim, we will use mouse and human genetics approaches to model biological pathways influenced by GPNMB and interrogate common downstream signaling pathways that mediate GPNMB effects on myocytes and non-myocytes. Finally, we will determine whether pharmacological targeting of GPNMB can be therapeutic strategy for attenuating adverse remodeling after cardiac injury.
/ RELVANCE TO PUBLIC HEALTH After a heart attack, dead heart muscle is replaced by scar tissue. Scar tissue induces cardiac remodeling that leads to dilatation of heart chambers and development of heart failure. In this application, we identify and target a novel gene GPNMB for attenuating cardiac remodeling.
