Targeting LARP6 in aging-associated heart failure - Aging with co-morbid conditions (i.e., obesity, hypertension) increases the risk of developing heart failure with preserved ejection fraction (HFpEF), and related cardiovascular morbidity and mortality for which there are few approved treatments. Importantly, HFpEF has become the most common form of HF and is characterized, in part, by cardiac fibrosis and reduced capillary density (i.e., rarefaction). Capillary rarefaction is associated with cardiac fibrosis in HFpEF and cardiac fibrosis is independently predictive of cardiac mortality in adults >70 years of age. LARP6 (La Ribonucleoprotein 6, Translational Regulator), an RNA binding protein, is implicated in pathologic fibrosis via binding to a unique 5' stem loop (5'SL) structure in collagen mRNA resulting in mRNA stabilization and increased translation, and excess collagen production/deposition. Our preliminary data provide the first evidence of LARP6-dependent cardiac fibrosis and dysfunction in response to chronic cardiac stress. Specifically, disruption of the LARP6-collagen mRNA interaction in a genetic (unique knock-in mouse model where the 5'SL region is mutated to prevent LARP6 binding; 5'SL mutant mice) and an interventional (the use of C9, a small molecule inhibitor of LARP6-collagen mRNA interaction) model each prevented cardiac fibrosis and contractile dysfunction following chronic β-adrenergic stimulation. Moreover, disruption of LARP6- collagen interaction promotes pro-angiogenic LARP6 signaling exhibited by increased capillary density and vasculogenic gene signatures in the heart. Lastly, cardiac LARP6 expression is increased in aging. Based on these `proof of concept' findings, we hypothesize that LARP6 signaling is a druggable target for the treatment of co-morbid aging-associated HFpEF. To test this hypothesis, we will utilize a `three-hit' mouse model of co- morbid aging-associated HFpEF to examine the following Specific Aims: Aim 1 will delineate the therapeutic potential of targeting LARP6-collagen interaction in cardiac fibrosis and dysfunction in lean and HFpEF 5'SL mutant mice/littermate controls (genetic) as well as lean and HFpEF C57BL/6J mice treated with C9 or vehicle (interventional). Cardiac morphology, function, and fibrosis in vivo by magnetic resonance imaging coupled with ex vivo analysis of fibrosis by staining and atomic force microscopy and assessment of LARP6 signaling will serve as major endpoints. Utilizing the same genetic and interventional models (5'SL mutant mice and C9), Aim 2 will elucidate the therapeutic potential of LARP6-Vegfa manipulation on capillary rarefaction and cardiac vasculogenic signaling in co-morbid aging-associated HFpEF. Capillary density, cardiac vascularity, analysis of cardiac pro-angiogenic mediator expression, delineation of the cardiac myocyte and non-myocyte transcriptome, and capillary sprouting in a tissue culture model are major endpoints. Together, the proposed conceptually innovative and translationally significant studies will provide novel evidence that disruption of LARP6-collagen interaction is a viable therapeutic target to attenuate cardiac fibrosis and enhance vascularity in co-morbid aging-associated HFpEF for which there are currently few approved treatments.
