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G protein-coupled receptor (GPCR) kinase 2 (GRK2) regulates members of the GPCR family, specifically cardiac β-adrenergic receptors. An increase in GRK2 is the primary clinical biomarker of congestive heart failure and its inhibition may be a significant therapeutic strategy to treat advanced of heart disease. Future research and further studies are required in order to determine if this is a realistic treatment option or just a theory in treatment.

Background Information
Cardiovascular disease is the number one fatal disease in North America. Congestive heart failure (HF) is a chronic syndrome characterized by dysregulated signalling of the sympathetic nervous system (SNS) and a decrease in left ventricular contractility leading to a reduction in cardiac output. Studies have shown a negative correlation between GRK2 protein expression and left ventricular function in patients with end-stage HF. This suggests that inhibition of the GRK2 signalling pathway may improve cardiac function following myocardial infarction. There is also evidence supporting a mechanism in which GRK2 activation is inhibited leading to the prevention and possible reversal of HF. A positive correlation may exist between an increase in GRK2 levels and the level of apoptotic cardiac enzymes. It has been shown that myocardial cell death is significantly increased with high levels of GRK2 due to elevated levels of these enzymes.

Mechanism of Action
The sympathetic branch of the autonomic nervous system releases neurotransmitters responsible for the regulation of blood pressure and heart rate. Norepinephrine and epinephrine, the two major catecholamines released via neurons in the SNS, stimulate adrenergic receptors. In early heart failure chronic activation of the SNS occurs as a compensatory mechanism in order to increase contractility and heart rate by upregulating the release of catecholamines. Increased circulating levels of norepinephrine and epinephrine have been shown to increase the activity of the cardiac GRK2 protein. High levels of GRK2 lead to the increased phosphorylation of GPCRs causing a conformational change in which receptor uncoupling occurs in cardiac myocytes. The decrease in activation that follows is termed 'desensitization' and is responsible for the reduced responsiveness of the receptors. The resulting dysfunction in the signalling pathway leads to a decrease in contractility of the heart, lowering blood pressure. The decrease in blood pressure is detected by chemoreceptors. In an attempt to compensate, an increased concentration of catecholamines are released thereby hyper-activating the β-adrenergic receptors in the heart. Therefore, increased GRK2 levels in HF cause detrimental effects on downstream pathways and it is this vicious cycle that drives the heart into a further diseased state.

Therapeutic Treatment
Research is now being directed towards the inhibition of GRK2 in both transgenic models and gene therapy modalities. Reducing levels of GRK2 aim to reverse HF symptoms by improving both cardiac structure and function and providing a cardioprotective effect against ischemia. Pharmacotherapy development shows a synergistic effect of a GRK2 inhibitor when used in combination with β-blockers. Pre-clinical trials have been conducted on transgenic animals with reduced GRK2 expression which show improved recovery after a myocardial infarction and exacerbation of HF progression. The cardiotoxic effects of SNS overstimulation leads to a hyperactive heart that chronically depletes energy stores and results in cardiac cell death. GRK2 is also present in the adrenal gland and has been found to decrease the amount of catecholamines within circulation. Adrenal GRK2 is a potential area for further research as decreased levels may slow the progression of heart failure.