Dapagliflozin Ameliorates Pulmonary Arterial Hypertension-Induced Right Heart Failure via Ketone Body Metabolism and Mitochondrial Function Enhancement.

BACKGROUND: Pulmonary arterial hypertension (PAH)-induced right ventricular (RV) failure increases reliance on ketones. The efficacy of SGLT2 inhibitors, known to modulate ketone metabolism, in this context remains unclear. METHODS: A PAH model was established in Sprague-Dawley rats via a single intraperitoneal injection of monocrotaline (MCT), followed by daily oral administration of dapagliflozin (DAPA). Pulmonary hemodynamics and RV function were evaluated using echocardiography and right heart catheterization. Myocardial injury, fibrosis, and mitochondrial ultrastructure were assessed via histological staining and transmission electron microscopy (TEM). Ketone body levels and metabolic enzyme expression were determined by ELISA and immunoblotting, with transcriptomic analysis identifying potential targets validated by rescue experiments. RESULTS: DAPA reduced pulmonary arterial pressure, improved RV systolic function, and attenuated RV hypertrophy and fibrosis. These benefits were associated with elevated β-hydroxybutyrate (β-OHB) and acetoacetate levels, alongside the upregulation of key ketone metabolic enzymes, including 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), β-hydroxybutyrate dehydrogenase 1 (BDH1), and succinyl-CoA:3-oxoacid CoA transferase (SCOT). Furthermore, DAPA restored mitochondrial homeostasis by increasing adenosine triphosphate (ATP) production, reducing oxidative stress, and shifting mitochondrial dynamics towards fusion-specifically by increasing mitofusin 1 (MFN1) and mitofusin 2 (MFN2), while decreasing dynamin-related protein 1 (DRP1) and fission 1 (FIS1). Transcriptomics revealed significant ADAMTS8 downregulation following DAPA treatment; crucially, adenovirus-mediated ADAMTS8 overexpression partially abrogated these cardioprotective effects. CONCLUSION: DAPA effectively alleviates PAH-induced right heart failure by suppressing ADAMTS8 expression, thereby enhancing myocardial ketone body metabolism and improving mitochondrial function. These findings identify ADAMTS8 as a key therapeutic target and provide novel evidence supporting the application of DAPA in PAH.