Failure of the right ventricle (RV) is a prevalent cause of cardiovascular morbidity and mortality, and the leading cause of death in patients with pulmonary hypertension. Moreover, RV failure frequently arises in patients with failure of the left ventricle (LV) and causes markedly worse symptoms and prognosis contrasted with patients with LV failure without RV dysfunction. Despite clinical significance, RV failure is relatively understudied, poorly understood and there i a need for more effective therapies to treat RV failure. We reported that the inotropic response to stimulation of ?1-adrenergic receptors (?1-ARs) is fundamentally different in the RV (negative inotropy) vs. LV (positive inotropy). Importantly, in RV failure, ?1-AR inotropic responses are upregulated and switched from a negative inotropic response in non-failing RV to a robust positive inotropic response in failing RV. This renewal project will build on the following recent observations: * Of the two major cardiac ?1-AR subtypes (?1A & ?1B), the dramatic switch from ?1-AR-mediated negative inotropy in non-failing RV to positive inotropy in failing RV is mediated solely by the ?1A-subtype but not the ?1B-subtype, suggesting that ?1A-subtype signaling is upregulated in failing RV. Consistent with beneficial effects mediated by the ?1A-subtype, in a model of RV failure, treatment for 2 wk. with the ?1A-subtype-specific agonist A61603 has major beneficial effects evidenced by improved in- vivo function, and reduced myocardial injury (evidenced by lower serum cardiac TnI, less myocardial fibrosis, and less ultrastructural cellular damage observed in electron micrographs). * Mechanistically, levels of reactive oxygen species (ROS) are elevated in failing RV, and our preliminary studies show that for failing RV, chronic treatment with A61603 increased levels of superoxide dismutase (SOD) and markedly reduced ROS. * ROS increases expression and activity of two intracellular isoforms of matrix-metalloproteinase-2 (MMP-2): the canonical full-length MMP-2 (FL-MMP-2) and a novel N-terminal truncated isoform (NTT-MMP-2). We reported that FL-MMP-2 impairs myocardial force by causing damage to the myofilaments. In contrast, we found that NTT-MMP-2 impairs myocardial force by impairing Ca2+ handling, without damage to myofilaments. * Chronic treatment with A61603 markedly reduces levels of FL-MMP-2 and NTT-MMP-2. Thus, for failing RV, ?1A-subtype-mediated lowering of FL-MMP-2 and NTT-MMP-2 levels may reduce damage to myofilaments and Ca2+ handling. Consistent with this, we found that for failing RV chronic treatment with A61603 increased myofilament function. 1. Hypothesis: For failing RV, chronic ?1A-subtype stimulation causes reduced ROS, which leads to decreased levels of FL-MMP-2 and NTT-MMP-2, and thereby, to reduced damage to myofilaments and Ca2+ handling. 2. Hypothesis: Chronic therapy with a ?1A-subtype agonist is beneficial in a chronic model of RV failure.
Aim 1. Determine the mechanisms for the beneficial effects of ?1A-subtype therapy in RV failure. For failing RV, we will determine if the beneficial effects of ?1A therapy with A61603 involves increased SOD, leading to reduced ROS, which results in lower levels of FL-MMP-2 and NTT-MMP-2, and thereby, reduced damage to myofilaments and Ca2+ handling.
Aim 2. Determine if chronic ?1A therapy has a beneficial effect on recovery of RV function in a chronic model of already established RV failure. Using a chronic pulmonary stenosis model of established RV failure, we will chronically treat mice for up to 20 wk. with A61603. We will determine if A61603 induces recovery of RV function and outcomes in chronic RV failure, and determine the mechanisms involved.

Public Health Relevance

Heart failure and chronic obstructive pulmonary disease (COPD) are extremely common in Veterans and commonly complicated by pulmonary hypertension and right heart failure. Treatment options for right heart failure are very limited. Heart failure has been the number one reason for admission among patients in the Veterans' Health Care System. Recent studies show that patients with post-traumatic stress disorder (PTSD) are at increased risk for cardiovascular disease, and PTSD is twice as prevalent in veteran populations versus the general population. The Department of Veteran Affairs Quality Enhancement Research Initiative (QUERI) is designed to improve care using research evidence to improve clinical practice for high-risk and/or highly prevalent diseases or conditions among veterans. Congestive heart failure is one of the high-risk, and highly prevalent diseases included in the QUERI program. Thus, research in cardiovascular disease, and RV failure in particular, are extremely important and relevant to the mission of the VA.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
2I01BX000740-05A1
Application #
9030974
Study Section
Cardiovascular Studies A (CARA)
Project Start
2010-04-01
Project End
2019-09-30
Budget Start
2015-10-01
Budget End
2016-09-30
Support Year
5
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Veterans Affairs Medical Center San Francisco
Department
Type
DUNS #
078763885
City
San Francisco
State
CA
Country
United States
Zip Code
94121
Myagmar, Bat-Erdene; Flynn, James M; Cowley, Patrick M et al. (2017) Adrenergic Receptors in Individual Ventricular Myocytes: The Beta-1 and Alpha-1B Are in All Cells, the Alpha-1A Is in a Subpopulation, and the Beta-2 and Beta-3 Are Mostly Absent. Circ Res 120:1103-1115
Ceron, Carla S; Baligand, Celine; Joshi, Sunil et al. (2017) An intracellular matrix metalloproteinase-2 isoform induces tubular regulated necrosis: implications for acute kidney injury. Am J Physiol Renal Physiol 312:F1166-F1183
Baligand, Celine; Qin, Hecong; True-Yasaki, Aisha et al. (2017) Hyperpolarized 13 C magnetic resonance evaluation of renal ischemia reperfusion injury in a murine model. NMR Biomed 30:
Simpson, Paul C; Myagmar, Bat-Erdene; Swigart, Philip M et al. (2017) Response by Simpson et al to Letter Regarding Article, ""Adrenergic Receptors in Individual Ventricular Myocytes: the Beta-1 and Alpha-1B Are in All Cells, the Alpha-1A Is in a Subpopulation, and the Beta-2 and Beta-3 Are Mostly Absent"". Circ Res 120:e56-e57
Thomas, R Croft; Singh, Abhishek; Cowley, Patrick et al. (2016) A Myocardial Slice Culture Model Reveals Alpha-1A-Adrenergic Receptor Signaling in the Human Heart. JACC Basic Transl Sci 1:155-167
Thomas Jr, R Croft; Cowley, Patrick M; Singh, Abhishek et al. (2016) The Alpha-1A Adrenergic Receptor in the Rabbit Heart. PLoS One 11:e0155238
Cowley, Patrick M; Wang, Guanying; Chang, Audrey N et al. (2015) The ?1A-adrenergic receptor subtype mediates increased contraction of failing right ventricular myocardium. Am J Physiol Heart Circ Physiol 309:H888-96
O'Connell, Timothy D; Jensen, Brian C; Baker, Anthony J et al. (2014) Cardiac alpha1-adrenergic receptors: novel aspects of expression, signaling mechanisms, physiologic function, and clinical importance. Pharmacol Rev 66:308-33
Lovett, David H; Chu, Charles; Wang, Guanying et al. (2014) A N-terminal truncated intracellular isoform of matrix metalloproteinase-2 impairs contractility of mouse myocardium. Front Physiol 5:363