Pathological cardiac hypertrophy is signaled largely through neurohormone receptor pathways transduced by the Gq heterotrimeric G-protein. The major terminal effectors of Gq signaling include Protein Kinase Cs (PKCs), and the major proximal signaling modulators include G-protein coupled Receptor Kinases (GRKs). Previously, we established that activation of GRKs and PKCs alters cardiomyocyte gene expression, cardiac contractility and ventricular remodeling in response to hemodynamic stress. We also have described clinical consequences of a functional GRK5 polymorphism in human heart failure. However, co-expression of multiple PKC and GRK kinase isoforms with overlapping and partially redundant functions in the heart has prevented clear delineation of isoform-specific GRK and PKC effects in heart disease. Doing so is important and timely for the following reasons: 1. Functional human GRK and PKC polymorphisms represent isoform-specific genetic perturbations whose consequences in health and disease need to be fully understood;2. Clinical and pre-clinical trials are already underway evaluating isoform-specific GRK2 and PKC? inhibition in cardiac ischemia and heart failure;and 3. A recent paradigm shift has revealed that GRKs not only terminate G- protein/PKC signaling, but concomitantly activate alternate G-protein-independent signaling through b- arrestins. For these reasons, we have developed novel floxed GRK and PKC isoform mice and used them to create unique cardiac-specific compound knockout models in which the individual effects of cardiac-expressed GRK2, GRK5, and GRK6, or of cardiac PKC? and PKC?, can be fully evaluated in the in vivo hypertrophying and failing heart. Our studies will critically examine the broad hypothesis that isoform-specific differential activation of G-protein-dependent PKC signaling and G-protein-independent GRK signaling pathways is a major determinant of the molecular, biochemical, and functional cardiac response to pressure overload. Using assays of gene expression, biochemical signal activity, protein expression, isolated cardiomyocyte function, and integrated cardiovascular function, we will systematically and comprehensively delineate isoform-specific GRK and PKC effects in developing, stable, and decompensating pathological (pressure overload) hypertrophy. The results of these functional genomics studies will move us closer to our long-term goal of more fully understanding the impact of neurohormonal/G-protein signaling on the heart, and of optimally directing existing and future therapeutics that interrupt such signaling in heart disease

Public Health Relevance

The reactive growth of cardiac muscle, termed cardiac hypertrophy, is a life-threatening condition common among patients with hypertension or after myocardial infarction. Some aspects of cardiac hypertrophy appear beneficial, like increased heart muscle that provides for greater pumping capacity. However, other aspects predispose to heart failure and sudden death, such as programmed cardiac myocyte death. Hypertrophy signaling is incredibly complex. Here, we will study unique genetic cardiac gene knockout mouse models that, for the first time, will help us identify and define specific drugable cardiac kinases that separately mediate beneficial and deleterious features of cardiac hypertrophy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL087871-07A1
Application #
8443487
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Adhikari, Bishow B
Project Start
2007-08-01
Project End
2017-01-31
Budget Start
2013-03-01
Budget End
2014-01-31
Support Year
7
Fiscal Year
2013
Total Cost
$448,826
Indirect Cost
$153,546
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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