Chronic SIRT1 supplementation in diabetic mice improves endothelial function by suppressing oxidative stress

Abstract

Aims Enhancing SIRT1 activity exerts beneficial cardiovascular effects. In diabetes, plasma SIRT1 levels are reduced. We aimed to investigate the therapeutic potential of chronic recombinant murine SIRT1 (rmSIRT1) supplementation in diabetic mice (db/db) to alleviate endothelial and vascular dysfunction. Methods and Results Left-internal mammary arteries from patients undergoing coronary artery bypass grafting (CABG) with or without a diagnosis of diabetes were assayed for SIRT1 protein levels. Twelve-week-old male db/db mice and db/+ controls were treated with vehicle or rmSIRT1 i.p. for 4 weeks, after which carotid artery pulse wave velocity (PWV) and energy expenditure/activity were assessed by ultrasound and metabolic cages, respectively. Aorta, carotid, and mesenteric arteries were isolated to determine endothelial and vascular function using myograph system. Arteries obtained from diabetic patients had significantly lower levels of SIRT1 than non-diabetic controls. Likewise, aortic SIRT1 levels were reduced in db/db mice compared to db/+ mice, while rmSIRT1 supplementation restored it to levels of controls. Mice treated with rmSIRT1 displayed increased physical activity and improved vascular compliance as reflected by reduced PWV and attenuated collagen deposition. Aorta of rmSIRT1-treated mice exhibited increased endothelial nitric oxide (eNOS) activity, and endothelium-dependent contractions of their carotid arteries were significantly decreased, while mesenteric resistance arteries showed preserved hyperpolarization. Ex-vivo incubation with reactive oxygen species scavenger (ROS) Tiron and NADPH oxidase inhibitor apocynin revealed that rmSIRT1 preserved vascular function by supressing NADPH oxidase (NOX)-related ROS sythesis. Chronic rmSIRT1 treatment suppressed the expression of NOX-1 and NOX-4, in line with a reduction in aortic protein carbonylation and plasma nitrotyrosine levels. Conclusions In diabetic conditions, arterial SIRT1 is reduced. Chronic rmSIRT1 supplementation improves endothelial function and vascular compliance by enhancing eNOS activity and suppresses NOX-related oxidative stress. Thus, SIRT1 supplementation may be a novel therapeutic strategy preventing diabetic vascular disease. Translational perspective The growing burden of obesity and diabetes drives an increasing portion of atherosclerotic cardiovascular disease, and represents a major challenge to public health. Herein, we probe the efficacy of recombinant SIRT1 supplementation to preserve endothelial function and vascular compliance during diabetic conditions. Notably, SIRT1 levels were diminished in diabetic arteries of mice and humans alike, while recombinant SIRT1 delivery improved energy metabolism and vascular function by suppressing oxidative stress. Our study deepens mechanistic insights into the vasculo-protective effects conferred by recombinant SIRT1 supplementation and opens therapeutic avenues to mitigate vascular disease in diabetic patients.

Sophocarpine alleviates doxorubicin-induced heart injury by suppressing oxidative stress and apoptosis

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Endothelial dysfunction in vascular complications of diabetes: a comprehensive review of mechanisms and implications

“…However, another study showed that SIRT1 promotes insulin secretion and pancreatic beta cell survival by interacting with FOXO, which can alleviate diabetes (35). Additionally, restoring aortic SIRT1 levels can significantly improve endothelial dysfunction and vascular compliance by enhancing eNOS activity and inhibiting NOX-associated oxidative stress (36). SIRT1 can improve vascular function in diabetes by deacetylating the 66-kDa Src homology 2 domain-containing protein (p66Shc) and reducing ROS production (37).…”

Ningxin-Tongyu-Zishen formula alleviates the senescence of granulosa cells on D-galactose-induced premature ovarian insufficiency mice

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