RECK in Adverse Cardiac Remodeling and Heart Failure

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According to the US Department of Veterans Affairs, heart failure (HF) and associated complications are one of the main reasons for hospital readmissions and death in the Veterans Healthcare System. In fact, above 40 years of age, the lifetime risk of developing HF is 1 in 5. Readmissions for HF occur within 30 days of discharge in 20% of patients older than 65 in the Medicare and Veterans. Together, these healthcare systems incurred nearly $37.2 billion for HF care. A substantial number of patients develop severe left ventricular hypertrophy (LVH) secondary to pressure overload (e.g., hypertension, aortic valve stenosis), and experience episodic severe congestive HF, hospitalization, and increased mortality. The mechanisms of HF are complex and include local and systemic neurohormonal changes and hemodynamic overload. RECK (Reversion Inducing Cysteine Rich Protein with Kazal motifs) is a unique membrane-anchored protein that inhibits many of the mediators responsible for adverse cardiac remodeling, including MMPs (matrix metalloproteinases), ADAMs (A Disintegrin and Metalloproteinase), EGFR, and inflammatory mediators. Our published reports demonstrated that angiotensin (Ang)-II, a critical mediator of hypertension-induced adverse cardiac remodeling, suppresses RECK in vivo. Moreover, Ang-II suppressed RECK and induced MMP activation and cardiac fibroblast migration in vitro, effects that were reversed by the ectopic overexpression of RECK. Our preliminary data show that pressure overload (PO) by transverse aortic constriction (TAC) suppresses RECK and increases MMP activation in a wild type mouse heart. While mice with inducible cardiomyocyte-specific RECK gene deletion spontaneously develop cardiac hypertrophy and fibrosis, and these effects are exacerbated by PO by TAC. In contrast, cardiomyocyte-specific RECK overexpression inhibits PO-induced hypertrophy, fibrosis and contractile dysfunction. Importantly, RECK expression is reduced in both hypertrophied (aortic stenosis) and failing human hearts of non-ischemic origin. Based on these critical and novel preliminary data, our central hypothesis is that reversing RECK suppression or enhancing its expression in the heart will blunt PO-induced adverse structural remodeling and progression to HF by targeting pro-hypertrophic and pro-fibrotic mediators. Our long-term goals are to understand the molecular mechanisms underlying the pathophysiology of myocardial hypertrophy and its transition to HF, and to identify novel therapeutic target(s) for intervention and treatment. Our immediate goals are to better characterize the cardioprotective role of RECK in inhibiting the pathogenesis of PO-induced adverse cardiac remodeling and HF development, and to develop an interventional strategy to induce its expression in the heart. To test our central hypothesis, three specific aims are proposed: In Aim 1, we will (a) Elucidate the impact of RECK deletion in a conditional cardiomyocyte-specific manner on spontaneous development of myocardial hypertrophy, fibrosis and dysfunction, and (b) determine whether RECK deletion exacerbates PO-induced adverse remodeling. In Aim 2, we will determine whether inducible cardiomyocyte-specific RECK overexpression will prevent the development of or reverse established PO-induced adverse cardiac remodeling and dysfunction, and progression to HF. In Aim 3, we will determine whether ectopic overexpression of RECK using an AAV9-based gene therapeutic approach will prevent the development of or reverse established PO-induced adverse cardiac remodeling and HF. Thus, our proposed genetic and gene therapeutic approaches will (i) delineate the fundamental role of RECK in cardiac structure and function, (ii) characterize its role as a critical anti-hypertrophic and anti-fibrotic mediator in PO, and (iii) demonstrate that its induction in the heart is a novel therapeutic approach to blunt progression of adverse structural and functional remodeling to heart failure.