Abstract 12425: Stim1 Deletion in Treg Cell Protects From HFpEF Pathogenesis

Abstract

Introduction: Heart failure with preserved ejection fraction (HFpEF) is a cardiovascular disease that remains untreatable in its pathogenesis. Therefore, there is a critical need to uncover the cellular and molecular mechanisms underlying HFpEF pathogenesis and identify potential targets for treatment that can enhance cardiac function and restrict disease progression. Previous studies have shown that Treg cells are crucial in hypertension-induced cardiovascular complications and metabolic dysregulation. Moreover, the function of Stromal interaction molecule 1 (STIM1) varies depending on the cell type. Hypothesis: We hypothesize that the deletion of STIM1 in Treg cells can protect against the development of HFpEF and its associated conditions. Methods: Male mice aged eight weeks (Stim1 flx/flx and Treg Stim1-/- ) were divided into four groups: control groups receiving a standard diet and water for five weeks, and HFpEF groups fed a high-fat diet (HFD) and N[w]-nitro-l-arginine methyl ester (L-NAME - 0.5g/L) in the drinking water for five weeks. Various measurements and assessments were conducted, including echocardiography, evaluations of metabolism and hypertension, analysis of heart and kidney injury markers, and assessment of vascular endothelial function. Results: After five weeks, Stim1 flx/flx mice subjected to HFD and L-NAME displayed evidence of HFpEF, including hypertension, metabolic disorders, cardiac hypertrophy with fibrosis, kidney injury with fibrosis, impaired exercise tolerance and vascular endothelial function, increased body weight and E/E' ratio, reduced cardiac index, and unchanged ejection fraction. Interestingly, Treg Stim1-/- mice were protected against HFD and L-NAME-induced HFpEF and its associated pathologies. Conclusions: These findings underscore the significance of targeting STIM1 in Treg cells to protect from the development and pathogenesis of HFpEF.