Abstract 33: Endoplasmic Reticulum Stress and Vascular Dysfunction in Hypertension

Abstract

Objective: Cardiac damage and vascular dysfunction are major causes of morbidity and mortality in hypertension. In this study, we explored the beneficial therapeutic effect of endoplasmic reticulum (ER) stress inhibition on cardiac damage and vascular dysfunction in hypertension. Methods & results: Mice were infused with angiotensin II (Ang-II, 400 ng/kg/min) with or without ER stress inhibitors (Tudca and PBA) for two weeks. Mice infused with Ang-II displayed an increase in blood pressure, cardiac hypertrophy and fibrosis associated with enhanced collagen-I content, TGFβ1 activity, and ER stress markers, which were blunted after ER stress inhibition. Hypertension induced ER stress in aorta and mesenteric resistance arteries (MRA), enhanced TGFβ1 activity in aorta but not in MRA, and reduced eNOS phosphorylation and endothelium-dependent relaxation (EDR) in aorta and MRA. The inhibition of ER stress significantly reduced TGFβ1 activity, enhanced eNOS phosphorylation and improved EDR. The inhibition of TGFβ1 pathway improved EDR in aorta but not in MRA, while the reduction in ROS levels ameliorated EDR in MRA only. Infusion of tunicamycin in control mice induced ER stress in aorta and MRA, and reduced EDR by a TGFβ1-dependent mechanism in aorta and ROS-dependent mechanism in MRA. Conclusion: ER stress inhibition reduces cardiac damage and improves vascular function in hypertension. Therefore ER stress could be a potential target for cardiovascular diseases.