RECK in Adverse Cardiac Remodeling and Heart Failure

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.

Grant Number: 5I01BX005845-04
NIH Institute/Center: VA
Principal Investigator: Chandrasekar Bysani