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The Role of Beta-Adrenergic Signaling in Cardiac Progenitor Cell Activation after Myocardial Infarction

Final Report Summary - HEART BETAS (The Role of Beta-Adrenergic Signaling in Cardiac Progenitor Cell Activation after Myocardial Infarction)

The objective of Heart Betas was to understand if resident cardiac progenitor cells (CPC) could be affected by β- adrenergic receptor signaling therapies that are critical in the current management of cardiovascular diseases. In particular, the general hypothesis proposed was that β2-adrenergic receptor signaling after a myocardial infarction (MI) favors the activation of endogenous CPC and thereby aids in improved cardiac remodeling. The first objective was to use a mouse model of MI to evaluate the response of CPC after treatment with β-adrenergic agonists/antagonists. The second objective was to investigate the hypothesis that β2-adrenergic signaling mediates CPC proliferation and migration through the regulation of intracellular calcium.

CPC β1 and β2 ARs expression was evaluated in vivo and in vitro. A significant increase in the percentage of CPCs expressing β1 and β2 ARs was measured 7 days post-MI. Accordingly, 24 hours of low serum and hypoxia in vitro significantly increased CPC β2 AR expression. Cell viability and differentiation assays validated a functional role of CPC β2 AR. The effect of pharmacological activation of β2 ARs was studied using fenoterol, administered in the drinking water either 1 week prior to MI or sham surgery or at the time of surgery. Immunofluorescence analysis of the heart tissue for proliferation, cardiomyocytes surface area, and vessel density showed significant changes based on surgery but no benefit due to fenoterol treatment. MI induced a significant increase in the percentage of CPC at 7 days, while pre-treatment with fenoterol prolonged this response resulting in a significant elevated number of CPC up to 21 days post-MI. Although cardiac function was not ameliorated when evaluated by echocardiography, infarct size was significantly reduced in mice pre-treated with fenoterol.

The final results of the project indicate that β2 adrenergic receptors can play a role in CPC proliferation and differentiation with their expression level adapting to stressful environments. In particular, in vivo stimulation of β2 adrenergic receptors significantly increased the local CPC pool in the myocardium and was associated with a decrease in infarct size, supporting the original hypothesis of the project. Myocardial infarction and ischemic heart disease continues to remain a significant societal and clinical problem. The results obtained in this fellowship offer insight on how to manipulate the endogenous healing process, potentially through better clinical pharmacological therapy and management, with the long-term aim of improving outcomes post-MI and hopefully lessening the burden in treating this disease.