Reply to the "Letter to the Editor" Ma Z-G, Yuan Y-P, Zhang X, Tang Q-Z. SGLT1: A potential target for human ischemic and hypertrophic heart?

Dear Dr. Tang, In our recently paper [1], we demonstrated that human hypertrophic and ischemic hearts are characterized by an increased expression of SGLT1 associated with increased phosphorylation/activation of different intracellular signalling pathways including AMPKα.We speculated these two phenomena might be linked, and that the activation of the intracellular energy sensor AMPK is a compensatory metabolic response to myocardial hypoxia and/or mechanical/metabolic stress. On the other hand, constitutive hyperactivation of AMPK is involved in the occurrence of hypertrophic cardiomyopathy in both humans [2] and transgenic mice [3]. In your letter, you further suggest that AMPKα acute activation protects fromhigh glucose-induced cardiomyopathy associated with diabetes and cardiac hypertrophy [4]. Indeed, AMPKα has recently been suggested to exert a critical dual role in the response to stimulated ischemia and reperfusion, depending on the energetic substrates available [5]. AMPKα activation is cardioprotective in the early reperfusion phase when glucose is the only available energetic substrate and, conversely, turns to exert a deleterious action in the later phases and in long term, when fatty acids are the dominant energy substrate. This novel observation, thus, may reconcile the biphasic/dual role of AMPKα in the heart disease. On the other hand, it is possible that SGLT1 inhibition plays a role in the cardiac effects of empagliflozin and other SGLT2 inhibitors; however, further research is needed to clarify this controversial point.