Arterial Destiffening Effects of SGLT2 Inhibition in Veterans with Obesity

/ABSTRACT Cardiovascular disease (CVD) is the main cause of death in the US, and its burden is rapidly growing in association with the obesity epidemic. Of note, not only the obesity rates are higher in the Veteran population, but also there is a higher level of the associated co-morbidities, including CVD, when compared to non- Veterans. A key vascular characteristic of obesity is arterial stiffening, which is a causal factor and independent prognosticator of cardiovascular morbidity and mortality. Even though increased arterial stiffness contributes to the pathogenesis of CVD, the mechanisms underlying arterial stiffening in obesity remain poorly understood. Further, there are currently no treatments available that directly target arterial stiffening. This project addresses these significant gaps in knowledge. Our long-term goal is to elucidate the molecular mechanisms causing obesity-related arterial stiffening that can be therapeutically targeted to prevent the development and/or reverse the progression of CVD. Arterial stiffening has been attributed to remodeling of the extracellular matrix of the vascular wall, particularly to increased deposition of adventitial collagen. However, the role of vascular smooth muscle cell (VSMC) stiffness in the pathogenesis of obesity-associated arterial stiffening is increasingly recognized. Based on rigorous published research and preliminary studies, the central hypothesis of this project is that VSMC activation of tissue transglutaminase (TG2) in obesity causes LIM kinase (LIMK)-dependent actin polymerization, stress fiber formation, and consequent arterial stiffening, an effect that can be reversed by inhibiting sodium glucose co-transporter 2 (SGLT2). A corollary to this hypothesis is that treating older adults with an SGLT2 inhibitor will reduce arterial stiffness. The hypothesis will be tested using gain- and loss-of-function genetic manipulation and pharmacological experiments in isolated arteries from Veterans with obesity and in cultured VSMC. Mechanistic studies will be complemented by a clinical trial to specifically test the efficacy of SGLT2 inhibition in reversing obesity-related arterial stiffening. Specifically, studies in Aim 1 will determine the role of VSMC TG2 activation and LIMK- dependent actin polymerization in arterial stiffening in obesity, and the effects of SGLT2 inhibition on this pathway. In Aim 2, the effects of empagliflozin, an SGLT2 inhibitor, on arterial stiffness in Veterans with obesity will be determined. It is posited that SGLT2 inhibition holds extraordinary promise for reversing arterial stiffening in obesity, and ultimately ameliorating CVD. Project Number: 1I01CX002859-01 | Fiscal Year: 2025 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: Jaume Padilla (+1 co-PI) | Institution: HARRY S. TRUMAN MEMORIAL VA HOSPITAL, COLUMBIA, MO | Activity Code: I01 | Study Section: Special Emphasis Panel[ZRD1 CARB-C (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11047997