The role of the beta3-adrenergic receptor in animal models of cardiac injury

Abstract

The β-adrenergic system is a key player in the regulation of the heart function. The role of the β1- and the β2- adrenergic receptors is well established and they are common targets of the medical treatment used in clinical practice. However the role of the β3-adrenergic receptor (β3AR) in the cardiovascular system is still poorly understood in both physiological and pathological conditions. It is known that β3AR expression in the heart is relatively low compared to β1 and β2 subtypes, nevertheless previous studies have shown that β3AR agonists have a cardioprotective effect in pressure overload hypertrophy, neurohormonal hypertrophic remodeling and ischemia/reperfusion injury. In the heart, β3ARs are present in cardiac myocytes and in endothelial cells but it is still unknown what is the relative contribution of these cell types in the cardioprotection afforded by the activation of the β3AR. Regarding heart failure little is known about the role of this receptor in the progression of cardiac dysfunction and contradictory results can be found in the literature. Recent results from the first-in-man clinical trial using a β3AR agonist in heart failure patients demand deeper knowledge about the role of the β3AR. The main aim of this doctoral thesis is to improve the knowledge concerning the β3AR in cardiac diseases. First, following an already existing research line in the laboratory we have investigated the cellular origin of the cardioprotection afforded by β3AR agonists administration before reperfusion. In this study we demonstrate for the first time using transgenic animal models never published before that β3AR activation in ischemia/reperfusion (IR) injury protects the heart by activating mainly the cardiomyocyte β3AR and not the endothelial β3AR. Moreover the overexpression of the receptor in cardiac myocytes amplifies the protection afforded by its activation, pointing out the β3AR overexpression as a potential therapy to reduce IR injury in patients at risk of acute myocardial infarction. Secondly, we have investigated the role of the β3AR in the progression of heart failure. Transgenic mice overexpressing the receptor in cardiac myocytes did not develop heart failure and gene therapy based overexpression of the receptor during the development of heart failure stopped its progression. We speculate that this protection involves increase in free fatty acids utilization by cardiac myocytes, inhibition of myocardial metabolism switch during heart failure and mitochondrial protection. This work confirms that β3AR stimulation is a therapy that should be considered to treat the failing heart. To conclude, this thesis increases the knowledge of the role of the β3AR in the cardiovascular system offering strong evidences of its therapeutic potential in the clinical arena as a target to decrease IR injury in patients with acute myocardial infarction and supporting the beneficial effect of its stimulation in the treatment of heart failure.