SGLT2 inhibition as a therapeutic strategy to reverse arterial stiffening in aging

PROJECT SUMMARY/ABSTRACT Cardiovascular disease (CVD) is the main cause of death in older adults in the US and the burden of aging- associated CVD is expected to grow as the percentage of the older population steadily grows. A key characteristic of vascular aging 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 aging remain poorly understood. Further, there are currently no treatments available that directly target arterial stiffening. This project addresses these significant gaps in knowledge. The long-term goal is to elucidate the molecular mechanisms causing aging-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) stiffening in the pathogenesis of aging-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 Ras homolog family member A (RhoA)/Rho-associated protein kinase (ROCK) in aging 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 younger and older individuals and in cultured VSMC. Mechanistic studies will be complemented by the first clinical trial to purposely test the efficacy of SGLT2 inhibition in reversing aging-related arterial stiffening. Specifically, studies in Aim 1 will determine the role of VSMC RhoA/ROCK activation and LIMK-dependent actin polymerization in arterial stiffening in aging, and the effects of SGLT2 inhibition on this pathway. In Aim 2, the effects of empagliflozin, an SGLT2 inhibitor, on arterial stiffness in older individuals will be determined. It is posited that SGLT2 inhibition holds extraordinary promise for reversing arterial stiffening in older adults, and ultimately ameliorating CVD.