Sodium-glucose Co-transporter 2 (SGLT2) inhibitor dapagliflozin acutely activates cardiomyocyte HIF-1α signaling via succinate, a signaling metabolite

SGLT2 inhibitors are widely used to treat patients with chronic heart failure, and several studies have shown that the efficacy of SGLT2 inhibitors also extends to acute heart failure. However, the mechanisms remain unknown. Here, using knockout mice and pharmacological approaches, we show that short-term SGLT2 inhibitor treatment activates hypoxia-inducible factor-1α (HIF-1α) signaling in cardiomyocytes, and further pharmacological studies raised the possibility that this effect is mediated by ketone body-derived succinate. One week of Dapagliflozin administration upregulated the expression of HIF-1α target genes, and the effect was abolished in cardiomyocyte-specific HIF-1α knockout mice. Metabolome analysis and enzyme-based assays revealed that, following one week of short-term Dapagliflozin treatment, ketone body levels in the heart increased, leading to an accumulation of succinate, which may act as a signaling metabolite that stabilizes HIF-1α. Administration of pimozide, which is a succinyl-CoA:3-ketoacid CoA transferase (SCOT) inhibitor that inhibits ketone body metabolism, abolished dapagliflozin-elicited activation of HIF-1α signaling. These results, although not conclusive, can be plausibly explained if short-term Dapagliflozin treatment activates HIF-1α signaling in cardiomyocytes via ketone body-derived succinate. Our study raises the possibility that HIF-1α plays a role in the effects of SGLT2 inhibitors and highlights HIF-1α as a speculative target for future studies.