Monomeric G-proteins and Cardioprotection from Heart Failure Heart failure incidence in the United States is steadily increasing with annual costs in excess of $30 billion and the cost is expected to increase 127% between now and 2030. Heart failure with reduced ejection fraction (HFrEF) occurs in ~45% of HF patients and is associated with longer survival compared to HF with preserved ejection fraction; however, treatment options are poor and are limited to increasing survival without improving systolic function. Success of agents, such as ?-blockers, to prolong lifespan (not necessarily quality of life) of HFrEF draws attention away from the fundamental principle that in HFrEF the heart defect is failure to contract with sufficient force to meet demand. This new proposal is motivated by our findings of a novel cardiac phenotype caused by deletion of the Rad-GTPase. Rad-null mice (Rad-/-) show increased cardiac contractility that persists well into senescence and out-performs age- and gender-matched animals. Rad-/- mice also show cardioprotection against chronic catecholamine stimulation, and against chronic pressure overload. In this proposal we will test two classes of potentially related but mutually exclusive mechanistic hypothesis. First, we will evaluate the contribution of altered Ca2+ homeostasis in response to Rad ablation; and second, we will assess Rad contributions to the ?-adrenergic receptor (?-AR) signaling axis. Three complementary Aims guide our studies. First, we will test the hypothesis that Rad-ablation confers enhanced function via sarcolemmal Ca2+ influx. These experiments will traverse scales of function from molecular to whole organ. Cardiac magnetic resonance imaging (CMR) and echocardiography will also be used to measure in vivo heart function. Second, we will evaluate the hypothesis that Rad deletion contributes to cardioprotection via enhancement of intracellular Ca2+ synchrony and preservation of ?-AR signaling. Again, assessments of heart structure and function will traverse scales from molecular, to cellular, to organ level and i vivo function.
Our third aim focuses on Rad-deletion as a potentially beneficial therapeutic approach. Overall, this proposal tests a novel mechanism of augmentation of cardiac function that confers cardioprotection against sustained pressure overload and chronic stress signaling.
Heart failure is a major health problem in the United States and a major risk factor is old age. By definition, heart failure involves the inability of the hear to generate sufficiently forceful contractions - defined as an insufficient inotropic response. This proposal tests a novel putative therapeutic direction that provides positive inotropic support to the failing myocardium along with protection against stress-induced remodeling.
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| Levitan, Bryana M; Manning, Janet R; Withers, Catherine N et al. (2016) Rad-deletion Phenocopies Tonic Sympathetic Stimulation of the Heart. J Cardiovasc Transl Res 9:432-444 |
