Targeting the HIF-1/ASC pathway with dapagliflozin protects against sleep apnea-exacerbated myocardial damage in heart failure

Introduction Intermittent hypoxia (IH), a hallmark of obstructive sleep apnea (OSA), exacerbates myocardial injury in chronic heart failure (CHF). Dapagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, has shown cardiovascular benefits, but its mechanisms in IH-related cardiac damage remain unclear. This study investigates the protective effects of dapagliflozin against IH-aggravated myocardial injury and explores its link to the HIF-1α/ASC signaling pathway. Purpose To evaluate the therapeutic potential and molecular mechanisms of dapagliflozin in mitigating IH-induced cardiomyocyte apoptosis, inflammation, and structural damage using in vitro (H9c2 cells) and in vivo (rat) models of CHF and OSA. Methods H9c2 cardiomyocytes were exposed to isoproterenol (ISO) to simulate CHF and IH to mimic OSA. Cell viability (MTT assay), apoptosis (flow cytometry), inflammatory cytokines (IL-6, CRP; ELISA), and HIF-1α/ASC pathway activity (Western blot, molecular docking) were analyzed. Rats received ISO injections for CHF induction and IH exposure for OSA modeling. Myocardial apoptosis (flow cytometry, Western blot for Bax, Bcl-2, Caspase-3), inflammation (plasma IL-6, CRP; ELISA), cardiac function (LVEF, LVDd; echocardiography), histopathology (HE staining), and ultrastructure (transmission electron microscopy) were assessed. Results IH exacerbated ISO-induced H9c2 cell damage (reduced viability, increased apoptosis) and elevated inflammatory markers (IL-6, CRP). Dapagliflozin pretreatment restored cell viability (MTT: P<0.05), reduced apoptosis (flow cytometry: P<0.05), suppressed inflammation, and inhibited HIF-1α/ASC pathway activation. Molecular docking confirmed stable binding of dapagliflozin to HIF-1α/ASC. In the animal study, rats with ISO-induced chronic HF and OSA (IH-exposed) exhibited aggravated myocardial apoptosis, structural disorganization (HE staining), elevated plasma IL-6/CRP, impaired cardiac function (reduced LVEF, increased LVDd; echocardiography), and ultrastructural damage (electron microscopy). OSA further activated the HIF-1α/ASC pathway, increasing pro-apoptotic proteins (Bax, Caspase-3) and reducing anti-apoptotic Bcl-2. Dapagliflozin intervention mitigated these changes, restoring cardiac function, alleviating myocardial injury, and suppressing HIF-1α/ASC signaling. Conclusions Dapagliflozin alleviates intermittent hypoxia-aggravated myocardial injury by inhibiting the HIF-1α/ASC pathway, thereby reducing apoptosis, inflammation, and structural deterioration in both cellular and animal models. These findings underscore its therapeutic promise for OSA-related cardiac complications in chronic heart failure.Schematic diagram