Role of inflammation and ER stress in HFpEF pathogenesis

Abstract

BackgroundHeart failure with preserved ejection fraction (HFpEF), characterized by diastolic dysfunction, inflammation, cardiac hypertrophy and fibrosis, myocardial capillary rarefaction, pulmonary hypertension, aortic stiffness, and impaired endothelial function, is the major unmet need in cardiovascular medicine and remains an untreatable cardiovascular disease. The role of inflammation and endoplasmic reticulum (ER) stress in HFpEF pathogenesis is not well understood.MethodsC57/Bl6 mice were divided into five groups. Group 1: control mice. Group 2: Mice fed high fat diet (HFD) and received L‐NAME (eNOS inhibitor,0.5 g/L) in the drinking water for 4 months. Group 3: Mice fed HFD + L‐NAME for 4 months then treated with ER stress inhibitor for one month (Tudca, 150 mg/Kg). Group 4: Mice fed HFD + L‐NAME then treated with anakinra for one month (IL‐1beta receptor antagonist, 1 µg/mouse/every other day). Group 5: Mice fed HFD + L‐NAME then treated with Tudca + anakinra for one month. We measured body weight, blood pressure, cardiac function, diabetes status, and vascular endothelial function.ResultsMice in group 2 fed HFD and L‐NAME in the drinking water for 4 months developed metabolic syndrome, hypertension, cardiac hypertrophy, lung edema, low running performance, vascular endothelial dysfunction, cardiac diastolic dysfunction, but no change in cardiac ejection fraction (EF) compared to group 1. Interestingly, the treatment of mice in groups 3, 4, and 5, with Tudca with and without anakinra provides protection from hypertension, body weight increase, metabolic syndrome, cardiac hypertrophy, lung edema, and vascular endothelial and diastolic dysfunction induced by HFD and L‐NAME.ConclusionOur data illustrate that ER stress and inflammation play a critical role in HFpEF pathogenesis.