Early cardioprotective effects of SGLT2i on hypertensive cardiac remodeling via STIM1/Orai1-dependent calcium signaling: beyond blood pressure control.

The cardioprotective effects of sodium-glucose cotransporter-2 inhibitors (SGLT2i) have attracted significant attention. The calcium ion signaling pathway influences various aspects of cellular function, store-operated calcium channels (SOCCs) serve as key calcium ion channels that induce cell apoptosis and exacerbate cardiac remodeling. This study aims to investigate the effects of SGLT2i on SOCCs and its potential cardioprotective mechanisms. Sprague-Dawley (SD) rats were sequentially treated with angiotensin II (Ang II) and dapagliflozin (Dapa), randomly divided into four groups: Sham, Dapa, Ang II, and Ang II + Dapa. Blood pressure, cardiac structure and function were measured. Cardiac fibrosis evaluated using Masson's trichrome staining. The apoptosis rate of H9C2 cells was determined by flow cytometry. Protein expression levels and functional activity of SOCCs were analyzed using Western blotting, calcium imaging, and fluorescence co-localization staining. In Ang II-induced hypertension rats, no significant blood pressure lowering effect of Dapa was observed within 28 days. Notably, the absence of blood pressure reduction did not affect the timely improvement of Ang II-induced cardiac remodeling by Dapa. Ang II enhanced store-operated calcium entry (SOCE), subsequently promoting cardiomyocyte apoptosis. Dapa administration effectively suppressed this pathological process by inhibiting the overexpression and overactivation of SOCC. SGLT2i improved early cardiac remodeling induced by Ang II without relying on antihypertensive effects, mainly by inhibiting excessive activation of SOCE, which effectively attenuated Ang II-triggered cardiomyocyte apoptosis. This provides a novel therapeutic paradigm targeting impaired myocardial calcium handling in hypertensive heart disease management.