Pathological cardiac hypertrophy (PCH) is an independent risk factor for lethal ventricular arrhythmias and heart failure. There is an unmet clinical need for more effective therapies to prevent or treat PCH. While PKA activation after sympathetic/?-adrenergic system stimulation is essential for the normal regulation of heart rate and cardiac contractility, persistent activation of sympathetic/?-adrenergic system/protein kinase A (PKA) in cardiovascular diseases such as hypertension leads to PCH and contractile dysfunction. However, it remains unclear how PKA promotes PCH and if manipulating PKA activation can be used to treat or prevent PCH. PKA activity is negatively regulated by endogenous PKA inhibitor peptides (PKI) in the heart. We found for the first time that one of the PKI isoform, PKI?, is concentrated in the nucleus of adult cardiomyocytes and keeps nuclear PKA activation less sensitive to stimulation and activated at a slower rate than cytosolic PKA. Furthermore, pressure overload reduces PKI? expression, especially in the nucleus, and its capability to inhibit PKA. When PKI? is genetically ablated in mice, nuclear PKA activity is enhanced, leading to surprisingly reduced PCH after pressure overload. On the other hand, when myocyte PKA is inhibited by only the PKA inhibition domain of PKI? (PKAi), PCH induced by pressure overload is blunted. Our cultured myocyte study suggest that this PCH reduction is related to cytosolic PKA inhibition. Therefore, we propose that the localization of PKA activation is crucial for its effect on the development of PCH. Depending on the cellular location (compartment) of PKA activation, PKA can either promote or blunt PCH induced by pressure overload. Based on these preliminary studies, we hypothesize that: while cytosolic PKA activation is prohypertrophic, nuclear PKA activation is antihypertrophic; endogenous PKI? exerts inhibition on nuclear PKA activation. We further predict that cytosolic PKA inhibition with enhanced nuclear PKA will be a desired strategy to prevent or treat PCH. We?ll test the hypothesis in three aims: 1) To determine the gene dose-dependent effects and mechanisms of global cardiomyocyte-specific PKA inhibition (PKAi) on cardiac structural and functional remodeling in response to hypertrophic stress. 2) To determine the effects of inhibiting cytosol PKA (with a cytosol-targeted PKAi) on PCH development. 3) To determine the effects of nuclear PKA activation by PKI? knockout or nuclear PKA overexpression or nuclear PKA inhibition on the development of PCH. The accomplishment of the proposed studies will provide novel insights into the roles of compartmental PKA and its regulation by PKI? in the development of PCH. New knowledge generated from this project will shed light into developing novel therapeutic strategy for the prevention and treatment of PCH in patients.

Public Health Relevance

Pressure overload such as hypertension leads to the pathological cardiac hypertrophy (PCH) with increased risk of lethal heart failure and arrhythmias. New approaches to prevent, treat or reverse cardiac hypertrophy are needed for these patients. This proposal aims to determine if, when and by what mechanisms inhibiting or activating protein kinase A (PKA) in the whole-heart cell or in part of the heart cell, i.e., the nucleus and the cytoplasm, may prevent or reverse the induction, progression and decompensation of PCH. We hypothesize that enhancing nuclear PKA and inhibiting cytosolic PKA can be used to prevent or treat PCH.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL140071-01A1
Application #
9595818
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Shi, Yang
Project Start
2018-07-01
Project End
2022-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Temple University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122