Right ventricular failure (RVF) is a serious clinical problem with a poor prognosis. However, specific treatment options for RVF are very limited. Recent studies suggest that powerful cardioprotective effects are mediated by ?1-adrenergic receptors, in particular the ?1A-subtype (?1A-AR). In the current funding period, we found that chronic stimulation of ?1A-ARs had major beneficial effects on RV function in two mouse models of RVF induced by pulmonary fibrosis or pulmonary artery constriction (PAC). This renewal project will identify the mechanisms involved in ?1A-AR-mediated reversal of RVF and investigate if the beneficial effects of chronic ?1A-AR stimulation extend to beneficial effects in human cardiac muscle preparations. This renewal project will build on the following preliminary results from the current funding period: In a model of RVF induced by PAC, RVF was reversed by chronic treatment with a highly specific ?1A- AR agonist (A61603), at a low dose that did not raise blood pressure. The beneficial effect of A61603 treatment involved increased signaling by the pro-survival kinase ERK, increased BCL-2 (anti-apoptosis factor that protects mitochondria), increased myocardial ATP levels, and decreased levels of reactive oxygen species (ROS), suggesting protective effects on mitochondria. RVF was associated with increased abundance of a novel intracellular isoform of matrix- metalloproteinase-2: N-terminal truncated MMP-2 (NTT-MMP-2). NTT-MMP-2 expression was reported to be induced by ROS and result in mitochondrial dysfunction, decreased ATP production and further ROS generation. Our preliminary results show that A61603 treatment reduces NTT-MMP-2 in mitochondria, and increased myocardial ATP, suggesting improved mitochondrial function. In the PAC model of RVF, chronic A61603 treatment decreased ROS, decreased ROS-mediated modification of myofilament proteins and increased myofilament force development. Preliminary studies using computational modeling suggest that increased myofilament force development is a critical factor in the improved RV function resulting from A61603 treatment. We recently reported that the ?1A-AR mediates a robust inotropic response in human RV myocardium from heart failure patients and that ?1A-AR-ERK signaling is present in failing human myocardium. These findings suggest that the ?1A-AR is present and functional in failing human RV and might be a therapeutic target to induce cardioprotective effects in patients with RVF. Hypothesis 1. For failing RV, chronic A61603 treatment rescues mitochondrial bioenergetic function, resulting in increased ATP levels, reduced ROS generation and increased contraction. Hypothesis 2. Rescue of mitochondrial bioenergetic function is mediated by reduced NTT-MMP-2 levels. Hypothesis 3. Chronic ?1A-AR stimulation is beneficial in human cardiac muscle preparations.
Aim 1. Determine if chronic A61603 treatment of RVF rescues mitochondrial bioenergetic function; leading to increased ATP levels, reduced ROS levels, increased myofilament contraction and rescue of RVF.
Aim 2. Determine if rescue of mitochondrial function is mediated by reduced levels of NTT-MMP-2. We will determine if chronic A61603 treatment of RVF reduces levels of NTT-MMP-2 and thereby rescues mitochondrial function. We will determine if inhibiting NTT-MMP-2 experimentally rescues mitochondrial function.
Aim 3. Determine if chronic treatment with A61603 has beneficial effects in human cardiac muscle preparations. As proof of principle for translation to humans, we will determine if chronic A61603 treatment has beneficial effects in two cardiac muscle preparations: engineered human heart tissue containing induced pluripotent stem cell (iPSC)-derived cardiomyocytes, and cultured RV trabeculae from RVF patients.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
2I01BX000740-09
Application #
9783206
Study Section
Special Emphasis Panel (ZRD1)
Project Start
2011-07-01
Project End
2023-09-30
Budget Start
2019-10-01
Budget End
2020-09-30
Support Year
9
Fiscal Year
2020
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
Pewowaruk, Ryan J; Philip, Jennifer L; Tewari, Shivendra G et al. (2018) Multiscale Computational Analysis of Right Ventricular Mechanoenergetics. J Biomech Eng 140:
Janssen, Paul M L; Canan, Benjamin D; Kilic, Ahmet et al. (2018) Human Myocardium Has a Robust ?1A-Subtype Adrenergic Receptor Inotropic Response. J Cardiovasc Pharmacol 72:136-142
Spaulding, Kimberly; Takaba, Kiyoaki; Collins, Alexander et al. (2018) Short term doxycycline treatment induces sustained improvement in myocardial infarction border zone contractility. PLoS One 13:e0192720
Philip, Jennifer L; Pewowaruk, Ryan J; Chen, Claire S et al. (2018) Impaired Myofilament Contraction Drives Right Ventricular Failure Secondary to Pressure Overload: Model Simulations, Experimental Validation, and Treatment Predictions. Front Physiol 9:731
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
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
Cowley, Patrick M; Wang, Guanying; Joshi, Sunil et al. (2017) ?1A-Subtype adrenergic agonist therapy for the failing right ventricle. Am J Physiol Heart Circ Physiol 313:H1109-H1118
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
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

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