Heart failure (HF) is a major clinical problem, with 1 million new cases per year, 1 million annual hospital admissions, a 50% 5-year mortality, and a role in 1 of 8 deaths. Little improvement in these statistics over recent decades indicates that current HF drugs could be improved. A classic feature of HF is elevation of cardiac sympathetic activity and circulating catecholamines, norepinephrine (NE) and epinephrine (EPI). NE and EPI activate 3 types of adrenergic receptors (ARs) on cardiac myocytes, β1, α1A, and α1B. Inhibition of excess, chronic β1 stimulation with beta-blockers is a key HF treatment, but the mechanisms of beta-blockers are incompletely understood, and there are no approved HF drugs that target α1-ARs. The overall goals of this project are to uncover novel adrenergic mechanisms in HF, and to further validate α1A adrenergic agonists as potential new drugs to treat HF. This project builds on 3 important novel findings from recent work. First, published data show that stimulation of an α1A-ERK pathway with drug agonists can treat HF in mouse models. Second, preliminary data suggest that beta-blockers can rescue NE and EPI activation of α1A-ERK cardioprotective signaling in cardiac myocytes. Third, published data show a novel model of ARs in ventricular myocytes, where all cells have the β1 and α1B, but only a 60% subset have the α1A, with high levels in only 20%. The β2 and β3 ARs are mostly absent in myocytes. Published data also show that α1-AR knockout decreases myocyte β1 ARs. These new findings raise several key questions regarding adrenergic mechanisms in HF: First, do beta-blockers work in part by rescuing α1A-ERK cardiorotective signaling by NE and EPI? Second, as a corollary, is the α1A receptor required for cardioprotection by beta-blockers? Third, what happens to myocyte β1 receptors downregulated in HF? Are β1 receptors lost selectively in the myocytes that do not have the α1A, and do α1A receptors protect or maintain β1 receptors? Fourth, if beta-blockers work in part by enhancing α1A-ERK signaling by endogenous NE and EPI, will an exogenous α1A agonist still have efficacy in the presence of a beta-blocker? Four specific aims are proposed to address these key questions: Aim I: Test the hypothesis that beta-blockers rescue α1A-ERK cardioprotective signaling by NE and EPI. We will use isolated ventricular myocytes from wild type (WT) and α1A knockout (KO) mice with HF from pressure overload transverse aortic constriction (TAC), and will examine a PKA-PP2A mechanism. Aim II. Test the hypothesis that cardiac myocyte α1A receptors are required for β-blocker efficacy in heart failure. We will compare beta-blocker rescue of TAC HF in WT and induced cardiac myocyte-specific α1A KO mice. Aim III: Test the hypothesis that α1A receptors protect β1-ARs in heart failure. We will use RT- qPCR to quantify α1A and β1 mRNAs in individual ventricular myocytes from TAC hearts. RNA sequencing will test a cardioprotective gene profile in α1A-expressing myocytes. Aim IV: Test the hypothesis that α1A agonist therapy adds efficacy to beta-blockade in heart failure. We will test the beta-blocker metoprolol in the absence or presence of the specific α1A agonist A61603 in a rescue protocol where treatment is started late after TAC, when cardiac function is reduced. RNA sequencing will test for differences in gene profiles with single and combined therapy. Successful completion of these Aims will uncover new adrenergic mechanisms in HF therapy, will provide crucial preclinical validation of a potential novel HF therapy with an α1A agonist, and will hopefully accelerate the translation to patients.

This project focuses basic research on the important cardiology problem of heart failure. Heart failure is the #1 discharge diagnosis in the VA Healthcare system. Current treatments are not very effective, and this project will test a potential new drug in an animal model of HF, and a possible new mechanism of an old drug. HF is often caused by ischemic heart disease, which is the 4th most common diagnosis in older Veterans, and is destined to become more and more prevalent, with the increase in Veterans with post-traumatic stress disorder (PTSD) and Agent Orange exposure. PTSD and Agent Orange are much more prevalent in Veterans, and both are recognized as causes of cardiovascular disease. The VA Quality Enhancement Research Initiative (QUERI) goal is to improve clinical practice for high-risk and/or highly prevalent diseases or conditions among Veterans. Heart failure and ischemic heart disease are both high-risk, and highly prevalent diseases included in the QUERI program. Thus research on heart failure is extremely important for the mission of the VA.