Sirt1 during childhood is associated with microvascular function later in life

Rodriguez‐Miguelez, Paula; Looney, Jacob; Thomas, Jeffrey; Harshfield, Gregory A.; Pollock, Jennifer S.; Harris, Ryan A.

doi:10.1152/ajpheart.00024.2020

Cited by 11 publications

(6 citation statements)

References 76 publications

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“…37 In humans, systemic lower circulating SIRT1 in childhood is associated with microvascular dysfunction during adulthood. 38 Our findings confirm the tight relationship between vascular SIRT1 and age-and metabolic-related microvascular endothelial function in A-D, Relaxing response to cumulative concentration to Ach in vessels precontracted with norepinephrine in the 4 groups (young nonobese: n=5; old nonobese: n=16; young obese: n=8; old obese: n=22). Vasodilatory response is expressed as % of the maximal diameter.…”

Section: Discussionsupporting

confidence: 84%

“… 37 In humans, systemic lower circulating SIRT1 in childhood is associated with microvascular dysfunction during adulthood. 38 Our findings confirm the tight relationship between vascular SIRT1 and age- and metabolic-related microvascular endothelial function in humans. They promote the hypothesis of SIRT1 as a crucial biological link between cellular energy availability, metabolism, and aging.…”

Section: Discussionsupporting

confidence: 82%

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Targeting SIRT1 Rescues Age- and Obesity-Induced Microvascular Dysfunction in Ex Vivo Human Vessels

Mengozzi

Costantino

Paneni

et al. 2022

Circulation Research

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BACKGROUND: Experimental evidence suggests a key role of SIRT1 (silent information regulator 1) in age- and metabolic-related vascular dysfunction. Whether these effects hold true in the human microvasculature is unknown. We aimed to investigate the SIRT1 role in very early stages of age- and obesity-related microvascular dysfunction in humans. METHODS: Ninety-five subjects undergoing elective laparoscopic surgery were recruited and stratified based on their body mass index status (above or below 30 kg/m 2 ) and age (above or below 40 years) and in 4 groups: Young Nonobese, Young Obese, Old Nonobese, and Old Obese. we measured small resistance arteries’ endothelial function by pressurized micromyography before and after incubation with a SIRT1 agonist (SRT1720) and a mitochondria reactive oxygen species scavenger (MitoTEMPO). We assessed vascular levels of mitochondria ROS and nitric oxide availability by confocal microscopy and vascular gene expression of SIRT1 and mitochondrial proteins by qPCR. Chromatin immunoprecipitation assay was employed to investigate SIRT1-dependent epigenetic regulation of mitochondrial proteins. RESULTS: Compared with Young Nonobese, obese and older patients showed lower vascular expression of SIRT1 and antioxidant proteins (FOXO3 [forkhead box protein O3] and SOD2) and higher expression of pro-oxidant and aging mitochondria proteins p66 Shc and Arginase II. Old Obese, Young Obese and Old Nonobese groups endothelial dysfunction was rescued by SRT1720. The restoration was comparable to the one obtained with mitoTEMPO. These effects were explained by SIRT1-dependent chromatin changes leading to reduced p66 Shc expression and upregulation of proteins involved in mitochondria respiratory chain. CONCLUSIONS: SIRT1 is a novel central modulator of the earliest microvascular damage induced by age and obesity. Through a complex epigenetic control mainly involving p66 Shc and Arginase II, it influences mitochondria ROS levels, NO availability, and the expression of proteins of the mitochondria respiratory chain. Therapeutic modulation of SIRT1 restores obesity- and age-related endothelial dysfunction. Early targeting of SIRT1 might represent a crucial strategy to prevent age- and obesity-related microvascular dysfunction.

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Section: Discussionsupporting

confidence: 84%

“… 37 In humans, systemic lower circulating SIRT1 in childhood is associated with microvascular dysfunction during adulthood. 38 Our findings confirm the tight relationship between vascular SIRT1 and age- and metabolic-related microvascular endothelial function in humans. They promote the hypothesis of SIRT1 as a crucial biological link between cellular energy availability, metabolism, and aging.…”

Section: Discussionsupporting

confidence: 82%

Targeting SIRT1 Rescues Age- and Obesity-Induced Microvascular Dysfunction in Ex Vivo Human Vessels

Mengozzi

Costantino

Paneni

et al. 2022

Circulation Research

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“…SIRT1 are not presently clear (36), circulating SIRT1 has also been shown to predict microvascular function (23), supporting the role of SIRT1 in the pathophysiology of endothelial dysfunction and the use of circulating SIRT1 as a novel biomarker to explore this association. In the present study, whereas oxLDL concentrations were similar, circulating SIRT1 was lower in the ACE þ than ACE À group (Fig.…”

Section: Discussionmentioning

confidence: 95%

“…In fact, SIRT1 has been shown to directly activate endothelial nitric oxide synthase (eNOS) (20) and inhibit endothelial oxidative stress (21,22). Accordingly, Rodriguez-Miguelez et al (23) recently reported that individuals with low circulating SIRT1 during childhood are more likely to exhibit premature vascular dysfunction in young adulthood. Therefore, it is plausible that aberrations in SIRT1 signaling and/or increased oxidative stress may contribute to ACEs-related impairments in vascular endothelial function (VEF).…”

Section: Introductionmentioning

confidence: 99%

Childhood psychosocial stress is linked with impaired vascular endothelial function, lower SIRT1, and oxidative stress in young adulthood

Jenkins

Rogers

Tomko

et al. 2021

American Journal of Physiology-Heart and Circulatory Physiology

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Adverse childhood experiences (ACEs) are psychosocial stressors that occur during sensitive developmental windows and are associated with increased lifetime cardiovascular disease (CVD) risk in a dose-dependent manner. Vascular endothelial dysfunction is a pathophysiological mechanism that promotes hypertension and CVD, and may be a mechanism by which ACEs contribute to lifetime CVD risk. We examined whether exposure to ACEs is associated with reduced vascular endothelial function (VEF) in otherwise healthy, young adult women (20.7 ± 3 years) with (ACE+) versus without (ACE-) ACEs, explored whether differences in circulating SIRT1 or systemic oxidative stress could explain ACEs-related differences in VEF, and examined the ability of a pilot, 8-week exercise intervention to augment VEF and SIRT1, or reduce oxidized LDL cholesterol (oxLDL) in ACE+ young adult women. Forty-two otherwise healthy young adults completed this study. Prior to the intervention, VEF (P = 0.002) and SIRT1 (P = 0.004) were lower in the ACE+ than ACE- group, but oxLDL concentrations were not different (P = 0.77). There were also significant associations (P ≤ 0.04) among FMD, SIRT1, and oxLDL in the ACE+, but not ACE- group. Adjusting for circulating SIRT1 and oxLDL reduced the differences in FMD observed between groups (P = 0.10), but only SIRT1 was a significant adjuster of the means (P < 0.05). The exercise intervention employed was unable to enhance VEF or SIRT1 in the ACE+ exercise group. Our data suggest that ACEs likely increase susceptibility to hypertension and CVD via reduced vascular function, perhaps through a SIRT1 pathway-related mechanism.

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“…Low SIRT1 levels early in life are associated with premature microvascular dysfunction during adulthood and increase the risk to develop CCVD. 158 Endothelial SIRT1deficient mice exhibit global endothelial dysfunction, underlying the development of microvascular and macrovascular complications. 159,160 Overexpression of SIRT1 in endothelial cells prevents age-induced impairment of vasodilator responses and inhibits vasoconstrictor responses to acetylcholine.…”

Section: Antivascular Aging Effects Of Endothelial Sirt1 Endothelial ...mentioning

confidence: 99%

Endothelial SIRT1 as a Target for the Prevention of Arterial Aging: Promises and Challenges

Begum

Konja

Singh

et al. 2021

Journal of Cardiovascular Pharmacology

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SIRT1, a member of the sirtuin family of longevity regulators, possesses potent activities preventing vascular aging. The expression and function of SIRT1 in endothelial cells are downregulated with age, in turn causing early vascular aging and predisposing various vascular abnormalities. Overexpression of SIRT1 in the vascular endothelium prevents aging-associated endothelial dysfunction and senescence, thus the development of hypertension and atherosclerosis. Numerous efforts have been directed to increase SIRT1 signaling as a potential strategy for different aging-associated diseases. However, the complex mechanisms underlying the regulation of SIRT1 have posed a significant challenge toward the design of specific and effective therapeutics. This review aimed to provide a summary on the regulation and function of SIRT1 in the vascular endothelium and to discuss the different approaches targeting this molecule for the prevention and treatment of age-related cardiovascular and cerebrovascular diseases.

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Sirt1 during childhood is associated with microvascular function later in life

Cited by 11 publications

References 76 publications

Targeting SIRT1 Rescues Age- and Obesity-Induced Microvascular Dysfunction in Ex Vivo Human Vessels

Targeting SIRT1 Rescues Age- and Obesity-Induced Microvascular Dysfunction in Ex Vivo Human Vessels

Childhood psychosocial stress is linked with impaired vascular endothelial function, lower SIRT1, and oxidative stress in young adulthood

Endothelial SIRT1 as a Target for the Prevention of Arterial Aging: Promises and Challenges

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