The Effect of Exercise on Endoplasmic Reticulum Stress-Associated Vascular Dysfunction



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Atherosclerosis and Alzheimer’s disease (AD) constitute a high health threat worldwide. Endothelial dysfunction is generally known as an early pathogenic response in atherosclerosis and a major culprit for the development of AD. Chronic endoplasmic reticulum (ER) stress in endothelial cells contributes to endothelial dysfunction with an increase in oxidative stress, inflammation, and apoptosis, which leads to cell death. Alleviation of ER stress in the vascular system can be an important therapeutic strategy for retardation and treatment of pathophysiology response in atherosclerosis and AD. Exercise training is considered to be frontline therapy for prevention and treatment of vascular dysfunction through the mitigation of oxidative stress and the inflammatory and apoptotic response in cardiovascular and neurodegenerative diseases. However, the role of exercise training in ER stress-associated vascular dysfunction in different vascular beds and its underlying mechanism in atherosclerosis and AD is still largely unknown. Therefore, the central aim of the dissertation study was to identify the underlying mechanisms by which exercise training mitigates ER stress-associated vascular dysfunction in different vascular beds and pathologies. To achieve the central aim of study, we investigated a comprehensive understanding of exercise effects on ER stress-associated endothelial dysfunction in different vascular beds (mesenteric artery and coronary arterioles) in atherosclerosis and on its molecular mechanisms. In addition, we explored the in-depth knowledge of the exercise effect on ER stress and purinergic receptor-associated cerebrovascular dysfunction using isolated intact posterior cerebral artery (PCA) from the transgenic mice model of AD and cultured human brain microvascular endothelial cells (HBMECs). To measure vascular function, we isolated the mesenteric arteries and coronary arterioles from ApoE knock-out mice for atherosclerosis and PCA from APP/PS1 double transgenic mice for AD. Also, we utilized programmed treadmill running as an exercise training intervention. To find an in-depth understanding of the exercise-induced effects at the cellular level, HBMECs were exposed to laminar shear stress (LSS). Our study demonstrates that ER stress impaired ACh-induced endothelial function in both mesenteric arteries and coronary arterioles of atherosclerosis through the reduction of eNOS expression and abnormal expression of ER stress markers, TXNIP/NLRP3 inflammasome, apoptosis, and oxidative stress. However, exercise training ameliorated ER stress-associated endothelial dysfunction in both vascular beds by reversing these abnormal molecular signaling pathways. In AD, ER stress impairs cerebrovascular function via the diminished eNOS expression, and increased ER stress markers and apoptosis expressions in AD mice brain, but exercise training improved cerebrovascular dysfunction by dampening these negative signaling cascades. Furthermore, ATP induced vasoconstriction in PCA from AD mice through the attenuation of eNOS and P2Y2 receptor expressions in AD mice brain. However, exercise training reversed ATP-induced vasoconstriction to vasodilation in PCA from AD mice with an increase in P2Y2 receptor-mediated eNOS signaling pathway in AD mice brain. Likewise, LSS upregulated the eNOS signaling and P2Y2 receptor expression in HBMECs, but inhibition of P2Y2 receptor blunted eNOS expression in LSS-induced HBMECs. The findings of this study will provide novel insight into the protective and therapeutic effect of exercise on ER stress- and purinergic receptor-associated vascular disease in atherosclerosis and AD.



ER stress, Vascular dysfunction, Exercise, Atherosclerosis, Alzheimer's Disease


Portions of this document appear in: Hong, Junyoung, Kwangchan Kim, Jong-Hee Kim, and Yoonjung Park. "The role of endoplasmic reticulum stress in cardiovascular disease and exercise." International journal of vascular medicine 2017 (2017). And in: Hong, Junyoung, Kwangchan Kim, Eunkyung Park, Jonghae Lee, Melissa M. Markofski, Sean P. Marrelli, and Yoonjung Park. "Exercise ameliorates endoplasmic reticulum stress-mediated vascular dysfunction in mesenteric arteries in atherosclerosis." Scientific reports 8, no. 1 (2018): 7938.