Abstract
Endoplasmic reticulum (ER) stress and uncoupling protein-2 (UCP2) activation are opposing modulators of endothelial dysfunction in atherosclerosis. Exercise reduces atherosclerosis plaques and enhances endothelial function. Our aim was to understand how exercise affects ER stress and UCP2 activation, and how that relates to endothelial dysfunction in an atherosclerotic murine model. Wild type (C57BL/6, WT) and apolipoprotein-E-knockout (ApoEtm1Unc, ApoE KO) mice underwent treadmill exercise training (EX) or remained sedentary for 12 weeks. Acetylcholine (ACh)-induced endothelium-dependent vasodilation was determined in the presence of an eNOS inhibitor (L-NAME), UCP2 inhibitor (genipin), and ER stress inducer (tunicamycin). UCP2, ER stress markers and NLRP3 inflammasome signaling were quantified by western blotting. p67phox and superoxide were visualized using immunofluorescence and DHE staining. Nitric oxide (NO) was measured by nitrate/nitrite assay. ACh-induced vasodilation was attenuated in coronary arterioles of ApoE KO mice but improved in ApoE KO-EX mice. Treatment of coronary arterioles with L-NAME, tunicamycin, and genipin significantly attenuated ACh-induced vasodilation in all mice except for ApoE KO mice. Exercise reduced expression of ER stress proteins, TXNIP/NLRP3 inflammasome signaling cascades, and Bax expression in the heart of ApoE KO-EX mice. Further, exercise diminished superoxide production and NADPH oxidase p67phox expression in coronary arterioles while simultaneously increasing UCP2 expression and nitric oxide (NO) production in the heart of ApoE KO-EX mice. Routine exercise alleviates endothelial dysfunction in atherosclerotic coronary arterioles in an eNOS, UCP2, and ER stress signaling specific manner, and resulting in reduced TXNIP/NLRP3 inflammasome activity and oxidative stress.
Highlights
Atherosclerosis is a major risk factor for cardiovascular disease and is one of the leading causes of death in the United States[1]
Neither initial nor maximal intraluminal diameters of coronary arterioles were significantly different in WT and atherosclerotic ApoE KO, and exercise training did not affect the diameters in either group (Table 1)
Our results demonstrate that the cardiovascular benefits of exercise are intimately linked to the relationship between Endoplasmic reticulum (ER) stress, Uncoupling protein-2 (UCP2), NLRP3 inflammasome, and oxidative stress
Summary
Atherosclerosis is a major risk factor for cardiovascular disease and is one of the leading causes of death in the United States[1] It is a chronic inflammatory disease of both small and large arteries and is characterized by largescale lipid plaques in vessel w alls[2]. Uncoupling protein-2 (UCP2) is a mitochondrial inner membrane protein that serves as an important negative regulator of mitochondrial-derived ROS production[6] It has emerged as an important antioxidant that prevents the development of atherosclerosis[7], as well as ameliorates endothelial dysfunction by increasing NO bioavailability in metabolic disorders[8]. It has been reported that thioredoxin-interacting protein (TXNIP) is a key factor linking ER stress to oxidative stress and inflammation[9] It is associated with endothelial dysfunction and the development of atherosclerosis[10]. Little is known about the mechanistic link between ER stress, TXNIP/ NLRP3 inflammasome activation, and UCP2 activity on coronary vascular dysfunction in atherosclerosis
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