Empagliflozin Reduces Post-Myocardial Infarction Inflammation via BDH1/β-Hydroxybutyrate-Mediated NF-κB Modulation in Macrophages and the Heart.

Abstract

Empagliflozin (EMPA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, demonstrates cardioprotective effects in heart failure, and recent trials suggest benefits in acute myocardial infarction (MI). However, the mechanisms underlying its efficacy, particularly its impact on the post-MI inflammatory response, are not fully elucidated. This study aimed to investigate whether EMPA modulates post-MI inflammation and to uncover the underlying molecular pathways. C57BL/6J mice undergoing MI were randomized to receive EMPA or saline for 7 days. EMPA treatment significantly improved survival, reduced fibrosis, and enhanced cardiac function. EMPA attenuated the systemic inflammatory response at day 1 post-MI, as evidenced by lower serum levels of IL-1β, IL-6, and CXCL-1. In the infarcted myocardium at day 1 post-MI, EMPA suppressed infiltration of neutrophils and pro-inflammatory macrophages while increasing anti-inflammatory macrophages. Mechanistically, EMPA upregulated the ketone body metabolic enzyme β-hydroxybutyrate dehydrogenase 1 (BDH1), increasing cardiac β-hydroxybutyrate (β-HB) levels, and subsequently inhibited NF-κB p65 phosphorylation. In immortalized bone marrow-derived macrophages, the anti-inflammatory effect of EMPA was mimicked by β-HB and abolished by Bdh1 knockdown, which was rescued by exogenous β-HB. In conclusion, EMPA attenuates maladaptive inflammation and confers cardioprotection after MI, potentially through a BDH1/β-HB/NF-κB pathway in macrophages. This ketone-mediated immunomodulatory axis, primarily defined in vitro, identifies a novel and potential​ pharmacological mechanism of SGLT2 inhibition in the context of post-MI inflammation.