Mol Med Rep. 2026 Aug;34(2):217. doi: 10.3892/mmr.2026.13927. Epub 2026 Jun 5.
ABSTRACT
Heart failure with preserved ejection fraction (HFpEF) is a common cardiovascular disorder characterized by a left ventricular ejection fraction of ≥45%, which is typically accompanied by diastolic dysfunction and symptoms of heart failure. Although dapagliflozin treatment may relieve symptoms in patients with HFpEF, the precise biological mechanisms underlying its therapeutic effects remain incompletely understood. Pyroptosis can induce inflammatory amplification and contribute to the development of cardiovascular disease. Nevertheless, the mechanism of dapagliflozin and pyroptosis in the pathogenesis and treatment of HfpEF remains largely unknown. The present study aimed to investigate the mechanism through which dapagliflozin regulates pyroptosis in HFpEF. First, a mouse model of HFpEF was established and dapagliflozin was administered to assess the phenotypes of HFpEF in mice and the level of pyroptosis in their myocardial tissues. Then, an HFpEF model of mouse cardiomyocytes was constructed, after which absent in melanoma 2 (AIM2) was knocked down and Caspase‑1 was overexpressed to determine the AIM2/Caspase‑1 signaling pathway in regulating pyroptosis under HFpEF conditions. Subsequently, cardiomyocytes were treated with dapagliflozin and AIM2 was overexpressed to investigate the mechanism by which dapagliflozin and AIM2 affect pyroptosis in HFpEF model cells. At the animal level, mice were treated with dapagliflozin and subjected to AIM2 overexpression to further explore the underlying mechanisms involved. Dapagliflozin alleviated the symptoms of HFpEF in mice and decreased the level of pyroptosis in the myocardial tissue of HFpEF mice. Compared with the sham group, AIM2 protein levels in the myocardial tissue of HFpEF mice were elevated and dapagliflozin treatment decreased AIM2 protein levels. Changes in pyroptosis in the myocardial tissue of HFpEF mice were accompanied by fluctuations in AIM2 protein levels. At the cellular level, AIM2 downregulation alleviated pyroptosis in mouse cardiomyocytes. Additionally, the data revealed a potential interaction between dapagliflozin and AIM2. Moreover, AIM2 regulated pyroptosis in mouse cardiomyocytes via the Caspase‑1/Gasdermin D (GSDMD) axis. Lastly, it was demonstrated in vitro and in vivo that dapagliflozin may alleviate HFpEF symptoms in mice through mechanisms involving regulation of the AIM2/Caspase‑1/GSDMD axis and attenuation of myocardial pyroptosis. In conclusion, dapagliflozin may alleviate HFpEF through mechanisms involving the AIM2/Caspase‑1/GSDMD axis to attenuate pyroptosis, suggesting a potential therapeutic approach for the treatment of HFpEF.
PMID:42246167 | DOI:10.3892/mmr.2026.13927