Activating P2Y1 receptors improves function in arteries with repressed autophagy.

Autor:	Cho JM; Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA.; Division of Endocrinology, Metabolism and Diabetes, Program in Molecular Medicine University of Utah School of Medicine, Salt Lake City, UT, USA., Park SK; Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA.; Division of Endocrinology, Metabolism and Diabetes, Program in Molecular Medicine University of Utah School of Medicine, Salt Lake City, UT, USA., Kwon OS; Department of Kinesiology, University of Connecticut, Storrs, CT, USA.; Department of Orthopedic Surgery & Center on Aging, University of Connecticut School of Medicine, Storrs, CT, USA., Taylor La Salle D; Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA.; Geriatric Research, Education, and Clinical Center, George E. Whalen Veterans Affairs Medical Center, Salt Lake City, UT, USA., Cerbie J; Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA.; Geriatric Research, Education, and Clinical Center, George E. Whalen Veterans Affairs Medical Center, Salt Lake City, UT, USA., Fermoyle CC; Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA.; Geriatric Research, Education, and Clinical Center, George E. Whalen Veterans Affairs Medical Center, Salt Lake City, UT, USA., Morgan D; Department of Anesthesiology, University of Utah, Salt Lake City, UT, USA., Nelson A; Geriatric Research, Education, and Clinical Center, George E. Whalen Veterans Affairs Medical Center, Salt Lake City, UT, USA., Bledsoe A; Department of Anesthesiology, University of Utah, Salt Lake City, UT, USA., Bharath LP; Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA.; Division of Endocrinology, Metabolism and Diabetes, Program in Molecular Medicine University of Utah School of Medicine, Salt Lake City, UT, USA., Tandar M; Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA., Kunapuli SP; Sol Sherry Thrombosis Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA., Richardson RS; Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA.; Geriatric Research, Education, and Clinical Center, George E. Whalen Veterans Affairs Medical Center, Salt Lake City, UT, USA.; Department of Internal Medicine, Division of Geriatrics, University of Utah, Salt Lake City, UT, USA., Anandh Babu PV; Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA., Mookherjee S; Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA.; Division of Endocrinology, Metabolism and Diabetes, Program in Molecular Medicine University of Utah School of Medicine, Salt Lake City, UT, USA., Kishore BK; Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA.; Nephrology Research, George E. Whalen VA Medical Center, Salt Lake City, UT, USA.; Department of Internal Medicine, Division of Nephrology, University of Utah, Salt Lake City, UT, USA., Wang F; Nephrology Research, George E. Whalen VA Medical Center, Salt Lake City, UT, USA.; Department of Internal Medicine, Division of Nephrology, University of Utah, Salt Lake City, UT, USA., Yang T; Nephrology Research, George E. Whalen VA Medical Center, Salt Lake City, UT, USA.; Department of Internal Medicine, Division of Nephrology, University of Utah, Salt Lake City, UT, USA., Boudina S; Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA.; Division of Endocrinology, Metabolism and Diabetes, Program in Molecular Medicine University of Utah School of Medicine, Salt Lake City, UT, USA., Trinity JD; Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA.; Geriatric Research, Education, and Clinical Center, George E. Whalen Veterans Affairs Medical Center, Salt Lake City, UT, USA.; Department of Internal Medicine, Division of Geriatrics, University of Utah, Salt Lake City, UT, USA., Symons JD; Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA.; Division of Endocrinology, Metabolism and Diabetes, Program in Molecular Medicine University of Utah School of Medicine, Salt Lake City, UT, USA.
Jazyk:	angličtina
Zdroj:	Cardiovascular research [Cardiovasc Res] 2023 Mar 17; Vol. 119 (1), pp. 252-267.
DOI:	10.1093/cvr/cvac061
Abstrakt:	Aim: The importance of endothelial cell (EC) autophagy to vascular homeostasis in the context of health and disease is evolving. Earlier, we reported that intact EC autophagy is requisite to maintain shear-stress-induced nitric oxide (NO) generation via glycolysis-dependent purinergic signalling to endothelial NO synthase (eNOS). Here, we illustrate the translational and functional significance of these findings. Methods and Results: First, we assessed translational relevance using older male humans and mice that exhibit blunted EC autophagy and impaired arterial function vs. adult controls. Active hyperaemia evoked by rhythmic handgrip exercise-elevated radial artery shear-rate similarly from baseline in adult and older subjects for 60 min. Compared with baseline, indexes of autophagy initiation, p-eNOSS1177 activation, and NO generation, occurred in radial artery ECs obtained from adult but not older volunteers. Regarding mice, indexes of autophagy and p-eNOSS1177 activation were robust in ECs from adult but not older animals that completed 60-min treadmill-running. Furthermore, 20 dyne • cm2 laminar shear stress × 45-min increased autophagic flux, glycolysis, ATP production, and p-eNOSS1177 in primary arterial ECs obtained from adult but not older mice. Concerning functional relevance, we next questioned whether the inability to initiate EC autophagy, glycolysis, and p-eNOSS1177in vitro precipitates arterial dysfunction ex vivo. Compromised intraluminal flow-mediated vasodilation displayed by arteries from older vs. adult mice was recapitulated in vessels from adult mice by (i) NO synthase inhibition; (ii) acute autophagy impairment using 3-methyladenine (3-MA); (iii) EC Atg3 depletion (iecAtg3KO mice); (iv) purinergic 2Y1-receptor (P2Y1-R) blockade; and (v) germline depletion of P2Y1-Rs. Importantly, P2Y1-R activation using 2-methylthio-ADP (2-Me-ADP) improved vasodilatory capacity in arteries from (i) adult mice treated with 3-MA; (ii) adult iecAtg3KO mice; and (iii) older animals with repressed EC autophagy. Conclusions: Arterial dysfunction concurrent with pharmacological, genetic, and age-associated EC autophagy compromise is improved by activating P2Y1-Rs. Competing Interests: Conflict of interest: None declared (© The Author(s) 2022. Published by Oxford University Press on behalf the of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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