Initiation of 3,3-dimethyl-1-butanol at midlife prevents endothelial dysfunction and attenuates in vivo aortic stiffening with ageing in mice.

Autor: Casso AG; Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, USA., VanDongen NS; Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, USA., Gioscia-Ryan RA; Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, USA., Clayton ZS; Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, USA., Greenberg NT; Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, USA., Ziemba BP; Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, USA., Hutton DA; Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, USA., Neilson AP; Department of Food Science and Technology, Virginia Tech, Blacksburg, Virginia, USA., Davy KP; Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Blacksburg, Virginia, USA., Seals DR; Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, USA., Brunt VE; Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, USA.; Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Jazyk: angličtina
Zdroj: The Journal of physiology [J Physiol] 2022 Nov; Vol. 600 (21), pp. 4633-4651. Date of Electronic Publication: 2022 Oct 13.
DOI: 10.1113/JP283581
Abstrakt: Vascular dysfunction: develops progressively with ageing; increases the risk of cardiovascular diseases (CVD); and is characterized by endothelial dysfunction and arterial stiffening, which are primarily mediated by superoxide-driven oxidative stress and consequently reduced nitric oxide (NO) bioavailability and arterial structural changes. Interventions initiated before vascular dysfunction manifests may have more promise for reducing CVD risk than interventions targeting established dysfunction. Gut microbiome-derived trimethylamine N-oxide (TMAO) induces vascular dysfunction, is associated with higher CV risk, and can be suppressed by 3,3-dimethyl-1-butanol (DMB). We investigated whether DMB supplementation could prevent age-related vascular dysfunction in C57BL/6N mice when initiated prior to development of dysfunction. Mice received drinking water with 1% DMB or normal drinking water (control) from midlife (18 months) until being studied at 21, 24 or 27 months of age, and were compared to young adult (5 month) mice. Endothelial function [carotid artery endothelium-dependent dilatation (EDD) to acetylcholine; pressure myography] progressively declined with age in control mice, which was fully prevented by DMB via higher NO-mediated EDD and lower superoxide-related suppression of EDD (normalization of EDD with the superoxide dismutase mimetic TEMPOL). In vivo aortic stiffness (pulse wave velocity) increased progressively with age in controls, but DMB attenuated stiffening by ∼ 70%, probably due to preservation of endothelial function, as DMB did not affect aortic intrinsic mechanical (structural) stiffness (stress-strain testing) nor adventitial abundance of the arterial structural protein collagen. Our findings indicate that long-term DMB supplementation prevents/attenuates age-related vascular dysfunction, and therefore has potential for translation to humans for reducing CV risk with ageing. KEY POINTS: Vascular dysfunction, characterized by endothelial dysfunction and arterial stiffening, develops progressively with ageing and increases the risk of cardiovascular diseases (CVD). Interventions aimed at preventing the development of CV risk factors have more potential for preventing CVD relative to those aimed at reversing established dysfunction. The gut microbiome-derived metabolite trimethylamine N-oxide (TMAO) induces vascular dysfunction, is associated with higher CV risk and can be suppressed by supplementation with 3,3-dimethyl-1-butanol (DMB). In mice, DMB prevented the development of endothelial dysfunction and delayed and attenuated in vivo arterial stiffening with ageing when supplementation was initiated in midlife, prior to the development of dysfunction. DMB supplementation or other TMAO-suppressing interventions have potential for translation to humans for reducing CV risk with ageing.
(© 2022 The Authors. The Journal of Physiology © 2022 The Physiological Society.)
Databáze: MEDLINE
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