Chembio spotlight #1
Paper: Inhibition of G-protein-coupled Receptor Kinase 2 Prevents the Dysfunctional Cardiac Substrate Metabolism in Fatty Acid Synthase
GRK-2: A potential target for therapeutic drugs treating Heart Failure
Heart Failure is a disabling syndrome that affects 6-10% of adults over the age of 65. It is caused by decreased performance of the heart in response to low blood pressure, increase in cardiac muscle and expansion of the left and/or right ventricles. Late stage-heart failure is associated with accumulation of fatty acids within the myocardial tissue resulting from metabolic changes in the heart. This change is the result of B oxidation decreases and in response the heart begins to rely on glycolysis for metabolic energy. Interestingly there is opposing evidence for the whether this shift is cardioprotective or damaging. The authors began their research by looking at FASN, the gene encoding fatty acid synthase which produces palmitate, a cardiolipotoxin, and is the possible link to the fatty acid accumulation during heart failure.
The authors use transgenic mice that express human FASN (tg-FASN) to show that the presence of FASN in myocardial tissue contributes to the occurrence of heart failure like symptoms and to a metabolic shift that is similar to human myocardial tissue during late stage-heart failure. As FASN has crucial functions in different types of tissues, it is a poor target for inhibition to potentially reduce its heart failure effects The authors instead target G-protein-coupled receptor Kinase 2 (GRK-2) for inhibition as it is a known cardioprotective and can regulate pparg through enhancement of ERK cascade activity as shown in figure 1. pparg is a transcription factor that positively regulates FASN and other gene targets, such as UCP1, that contribute to heart-failure-like symptoms. The authors develop an inhibitor for GSK-2 (GRKInh) to develop tg-GRKInh/FASN mice and find that the GRK-2 inhibitor delays the occurrence of heart failure compared to tg-FASN mice and prevents the metabolic shift to glycolysis that occurs in tg-FASN without the GSK-2 inhibitor by increasing the rate of B oxidation given by relative OCR and ECAR. Using and ERK cascade inhibitor (RKIP), the authors confirm that the GSKInh is down-regulating pparg via the ERK cascade which inactivates pparg by phosphorylation at serine-273. The evidence proposed by this study suggest that the metabolic shift that occurs in late-stage heart failure are actually detrimental to myocardial health and that inhibition of FASN can increase B oxidation and subsequently decrease palmitate thereby preventing lipid overload and cardiomyocyte death. The proposed pathway provides great evidence for the potential of a therapeutic drug that targets GRK-2 in myocardial tissue in the treatment of Heart Failure.
Abd Alla, J., Graemer, M., Fu, X. & Quitterer, U. Inhibition of G-protein-coupled Receptor Kinase 2 Prevents the Dysfunctional Cardiac Substrate Metabolism in Fatty Acid Synthase Transgenic Mice. Journal of Biological Chemistry 291, 2583–2600 (2016).
John JV McMurray, Marc A Pfeffer, Heart failure, The Lancet, Volume 365, Issue 9474, 28 May–3 June 2005, Pages 1877-1889, ISSN 0140-6736, http://dx.doi.org/10.1016/S0140-6736(05)66621-4.