SGLT2i continuously prevents cardiac hypertrophy by reducing ferroptosis via AMPK up-regulation.

Abstract

Cardiac hypertrophy is an independent risk factor and prognosis indicator of heart failure. Early intervention of cardiac hypertrophy is crucial to prevent heart failure and improve patients' outcomes. Despite evidence that activation of AMPK (adenosine monophosphate-activated protein kinase) plays a protective role in cardiac hypertrophy, whether it plays a sustained role and the precise mechanism remains unexplored. We established in vivo model of cardiac hypertrophy by coarctation of rat abdominal aorta (AAC-CH model). SGLT2 inhibitor (SGLT2i) was used to activate AMPK and cardiac function was evaluated after 2, 4, 8, 12 weeks. Animals were killed, and cardiac tissue was examined for morphological changes, fibrosis, and ferroptosis. At 2 weeks, rats already had histopathological abnormalities including enlarged cardiomyocytes, cardiac fibrosis, and ferroptosis, which persisted overtime. However, these changes were remarkably prevented by the treatment of SGLT2i. Then, we established in vitro model of cardiac hypertrophy by treating H9C2 cells with isoproterenol (ISO,10 µM). Unexpectedly, mechanistic studies revealed that antagonism of AMPK aggravated oxidative stress and ferroptosis, reduced GPX4 (glutathione peroxidase 4) level, and partially abolished the anti-hypertrophic and anti-ferroptosis effects of SGLT2i in H9C2 cells. Taken together, the regulatory role between AMPK and ferroptosis was revealed for the first time in cardiac hypertrophy. SGLT2i counteracts ferroptosis by activating AMPK, providing a sustained protection against cardiac hypertrophy. This positions SGLT2i as a potential therapeutic agent for the treatment of cardiac hypertrophy. Besides, in addition to the downregulation of AMPK in hypertrophic heart tissue, its levels are also reduced in plasma, suggesting its potential to serve as a diagnostic marker for the early detection of ferroptosis and cardiac hypertrophy.