SGLT2 inhibitors after myocardial infarction: Beyond glycemic control to inflammasome modulation

Title : SGLT2 inhibitors after myocardial infarction: Beyond glycemic control to inflammasome modulation

Abstract:

Heart failure remains a major complication following myocardial infarction (MI), driven in part by sterile inflammation and adverse ventricular remodeling. While sodium-glucose cotransporter-2 (SGLT2) inhibitors have demonstrated robust cardiovascular benefits independent of glycemic control, the underlying mechanisms remain incompletely defined. Emerging evidence suggests a role for inflammasome modulation, particularly the TXNIP/NLRP3 axis, in mediating these effects.

Objective: To investigate whether SGLT2 inhibition attenuates myocardial injury after MI through suppression of the TXNIP/NLRP3 inflammasome pathway.

Methods: A rat model of left anterior descending (LAD) coronary artery ligation was used to induce MI. Animals were randomized to receive vehicle or dapagliflozin (5 or 10 mg/kg) administered 1 hour post-MI. Outcomes were assessed at 72 hours, corresponding to peak inflammatory activation. Infarct size was quantified by triphenyltetrazolium chloride (TTC) staining. Protein expression of TXNIP, NLRP3, and IL-1β was evaluated by Western blot. Cardiac injury markers (troponin, BNP) and hemodynamic parameters were also measured. Mechanistic validation was performed using CRISPR-mediated overexpression of TXNIP or NLRP3.

Results: Dapagliflozin significantly reduced infarct size by approximately 20% compared to MI controls. This was accompanied by marked suppression of TXNIP and NLRP3 expression, as well as decreased IL-1β levels, indicating functional attenuation of inflammasome signaling. Cardiac injury markers, including troponin and BNP, were significantly reduced. Importantly, CRISPR-mediated activation of TXNIP or NLRP3 reversed the cardioprotective effects of dapagliflozin, restoring infarct size and inflammatory signaling toward untreated MI levels. No significant differences in blood pressure or heart rate were observed, and all experiments were conducted in non-diabetic animals, supporting a glucose-independent mechanism.

Conclusion: SGLT2 inhibition confers cardioprotection following MI through suppression of the TXNIP/NLRP3 inflammasome pathway. This effect is mechanistically required, independent of glycemic control and hemodynamic changes. These findings suggest that SGLT2 inhibitors may function as early modulators of sterile inflammation, highlighting their potential role in limiting post-MI injury and preventing progression to heart failure.

Biography:

Desislava Doycheva, PhD is an Assistant Professor in the Department of Cardiology at Loma Linda University. She has over a decade of experience in translational neuroscience and cardiovascular research, with extensive expertise in small-animal disease models, molecular biology, and mechanistic studies of ischemic injury. Her earlier work focused on neonatal hypoxic–ischemic encephalopathy and ischemic stroke, where she contributed to multiple NIH- and AHA-funded studies investigating endoplasmic reticulum stress, inflammation, and neuroprotection.

In recent years, she has expanded her research program into cardiovascular disease, leading studies in rat myocardial ischemia–reperfusion models to investigate the anti-inflammatory and cardioprotective mechanisms of sodium–glucose cotransporter-2 (SGLT2) inhibitors. Her current work examines both acute and chronic SGLT2 inhibitor treatment in diabetic and non-diabetic myocardium, with a particular focus on TXNIP/NLRP3 inflammasome signaling, oxidative stress, and post–myocardial infarction remodeling. She has authored over 50 peer-reviewed publications and is actively involved in NIH and American Heart Association grant development, mentoring, and collaborative translational research.