Right Heart Function in Health and Chronic Lung Disease

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DESCRIPTION (provided by applicant): Failure of the right ventricle (RV) is a prevalent cause of cardiovascular morbidity and mortality. However, RV failure is relatively understudied and poorly understood, thus there is a need for greater understanding of the pathophysiology of RV failure. We reported that inotropic regulation is distinctly different in the RV than the LV. Moreover, our new preliminary studies suggest that inotropic regulation of the RV is affected very differently in heart failure compared to the LV. We found that in failing RV the inotropic response to norepinephrine (NE, a mixed 1/2 agonist) was appreciably increased, despite downregulation of 2-responses; thus, suggesting upregulation of responses to alpha-1 adrenergic receptors (11-ARs). Consistent with this, we recently reported that in failing RV the inotropic response to 11-AR agonism is increased. Mechanistically, we found that myosin light chain kinase (MLCK), which is activated by 11-ARs, is increased in the failing RV. Increased MLCK might contribute to increased inotropic responses in the failing RV by causing increased phosphorylation of the contractile protein myosin light chain-2 (MLC2), and consequently, increased myofilament Ca2+ sensitivity. Based on preliminary results, we will test two hypotheses: 1) In RV failure, increased 11-AR inotropy compensates for 2-AR downregulation to mediate increased inotropic responses to the natural catecholamine NE; 2) In RV failure, therapies to further increase 11-AR signaling will improve RV function and outcomes. This project has a "mechanism aim" to determine the basis of increased inotropic responses in failing RV; and a "translational aim" to study a new therapeutic approach for RV failure. We will study the RV-specific model of bleomycin-induced pulmonary fibrosis, which leads to pulmonary hypertension and RV failure. Aim 1. Determine the role of 11-AR signaling in mediating an increased RV inotropic response to NE in RV failure. For increased RV responses to NE in a RV-specific heart failure model, we will determine the roles of: 11-ARs, 11-AR subtypes (using knockouts), MLCK-induced phosphorylation of MLC2 (using a loss of function mutant), and increased myofilament Ca2+ sensitivity. We will determine the relevance to human disease by studying samples from failing and nonfailing human hearts using the "UCSF Living Heart Resource" that was recently funded by a NIH Challenge Grant to procure failing and nonfailing human hearts for physiologic study (the PI is Co-PI on this Challenge Grant). Aim 2. Determine if therapeutically increased 11A-AR subtype signaling has a beneficial effect on RV function and outcomes in RV failure. Using an RV-specific heart failure model, we will chronically treat mice with a low dose of the 11A-AR subtype-specific agonist A61603. We will determine if A61603 improves RV function and outcomes in RV failure, and determine the mechanisms involved. To determine the 11A-AR- specificity of improvements with A61603, we will determine if the 11A-AR is necessary by using knockout mice lacking the 11A-AR subtype; and determine if the 11A-AR is sufficient by using mice expressing only the 11A-AR. These studies will be significant for understanding and treating human disease. In heart failure, where catecholamines are elevated, upregulation of RV inotropic responses might help the RV adapt to increased pulmonary pressures. Moreover, in heart failure, inotropic regulation of the RV (increased inotropy) differs fundamentally from the LV (decreased inotropy), suggesting that new approaches for treating RV failure could be tailored to the distinctive physiology of the RV. This project will explore such a new approach. PUBLIC HEALTH RELEVANCE: Heart failure is a serious disease affecting significant numbers of veterans. The heart is composed of two sides (left and right), each with a main pumping chamber called a ventricle. Failure of the left ventricle (LV) has been extensively studied. However, failure of the right ventricle (RV) is relatively understudied and poorly understood. This is a significant gap in knowledge, because RV failure is frequently present in patients with heart failure. This project arises from our discovery that heart failure affects the RV quite differently than the LV. This grant application will have a "mechanistic aim" to investigate the basis for the novel responses to heart failure that we have discovered in the RV. Moreover, we also propose a "translational aim" to investigate a new approach to treat the failing RV. This grant will increase our understanding of a significant and devastating disease, and focus on discovery of new approach to treatment.