Despite complete revascularization by coronary artery bypass grafting (CABG), long-term survival is markedly inferior for patients who present with depressed left ventricular function post-myocardial infarction. Adverse or maladaptive ventricular remodeling can continue following revascularization and appears to be an important risk factor for poor long-term outcomes after CABG with progression to HF. Cardiac fibroblasts (CF) make up 60-70% of the total cell mass of the heart and play a critical role in regulating normal myocardial function and in the adverse remodeling that occurs with myocardial infarction and the transition to HF. Excessive collagen deposition by CF leads to myocardial stiffening, diastolic dysfunction, and overload of the heart, likely as a consequence of transformation of quiescent fibroblasts responsible for basal extracellular matrix (ECM) homeostasis to activated myofibroblasts (myoFb). Approaches to inhibit this transformation are needed in tissues, such as the heart, where excessive ECM production by CF leads to fibrosis and remodeling which is a precursor to HF. Recent work has demonstrated that increased intracellular cAMP and downstream activation of cAMP-dependent protein kinase (PKA) can inhibit myoFb formation and collagen synthesis in vitro. The primary mechanism for cAMP production in CF is through stimulation of membrane-bound 22-adrenergic receptors which couple to adenylyl cyclase. Recent data from our laboratory show that 2-adrenergic receptor (2-AR) signaling and cAMP production are severely impaired in CF isolated from ventricles of patients with advanced HF and may be a critical underlying mechanism for myoFb formation and increased ECM deposition. We have found that G protein-coupled receptor kinase-2 (GRK2), a serine-threonine kinase that phosphorylates and uncouples agonist-occupied 2-ARs, is robustly expressed in CF and GRK2 activity is significantly upregulated in chronic HF. The long-term goal of this project is to specifically delineate the roles of 2-AR signaling and GRK2 in adult CF transformation to myoFb with the aim of inhibiting or minimizing pathological fibrosis that can lead to HF post-myocardial infarction despite successful revascularization. Our central hypothesis is that impaired 2-AR signaling, as a result of increased GRK2 activity, mediates CF to myoFb transformation and increases ECM synthesis. Thus, impaired CF 2-AR signaling promotes maladaptive remodeling and progressive cardiac dysfunction contributing to HF. This will be tested using molecular approaches to knockdown and over express GRK2 in CF isolated from normal and failing human ventricles to investigate the role of GRK2 in regulating CF activation. In vivo studies will be performed in a rat myocardial infarction model using adeno-associated viral gene transfer of a mini-gene inhibitor of GRK2 in a CF-specific manner to achieve long-term expression and evaluate potential therapeutic efficacy in inhibiting adverse remodeling and improving cardiac function and survival. Inhibition of GRK2 activity has important therapeutic promise in this disease process and may represent a novel adjunctive therapy at the time of CABG.

Public Health Relevance

The proposed research is relevant to public health because the discovery of a novel adjunctive therapy which could be delivered at the time of coronary artery bypass surgery to inhibit the potential transition to heart failure in patients who have suffered a pre-operative myocardial infarction could lead to significantly greater quality of life and long-term survival. This research may also be relevant to preventing fibrosis of other organs which also contribute to significant morbidity and mortality.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Keleti, Julianna
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University of Chicago
Schools of Medicine
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Li, Jinju; Philip, Jennifer L; Xu, Xianyao et al. (2014) ?-Arrestins regulate human cardiac fibroblast transformation and collagen synthesis in adverse ventricular remodeling. J Mol Cell Cardiol 76:73-83
Prochaska, Micah T; Bergl, Paul A; Patel, Amit R et al. (2013) Atrioventricular heart block and syncope coincident with diagnosis of systemic lupus erythematosus. Can J Cardiol 29:1330.e5-1330.e7