Emerging role of SIRT3 in endothelial metabolism, angiogenesis, and cardiovascular disease

He, Xiaochen; Zeng, Heng; Chen, Jianxiong

doi:10.1002/jcp.27200

Cited by 85 publications

(78 citation statements)

References 147 publications

(296 reference statements)

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“…Sirtuins are important regulatory elements of energy metabolism and antioxidative defense, using post-translational modifications [32,52,73,74]. Sirtuins were recently shown to regulate vascular and especially endothelial functions, under physiological conditions [1][2][3][4]. Dysregulation of sirtuins was observed under pathophysiological conditions like cardiovascular disease [20][21][22][23][24] and vascular aging, including atherosclerosis [1,[25][26][27][28].…”

Section: Discussionmentioning

confidence: 99%

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Impact of Short-Term Hypoxia on Sirtuins as Regulatory Elements in HUVECs

Pecher

Potthast

Versen‐Höynck

2020

JCM

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Background: Sirtuins (SIRT) are NAD+-dependent deacetylases that are involved in stress response, antioxidative defense, and longevity via posttranslational modifications. SIRT1 directly activates nitric oxide synthase (NOS). Aging is associated with a reduced sirtuin function and reduction of the cofactor NAD+. Age-related atherosclerosis and vascular diseases are linked to a compromised sirtuin function. Vascular events like stroke and cardiac infarction result in acute hypoxia, which can additionally impact sirtuins and thus the vascular function. This prompted us to study sirtuins in intact HUVECs, under acute, short-term hypoxic conditions. Methods: We measured intracellular sirtuin and NAD+ levels in HUVECs exposed to hypoxia (2% O₂) for 10–120 min, compared to normoxic controls. SIRT1, SIRT3, and SIRT4 were measured at the protein (Western Blot) and the transcript level (qRT-PCR), SIRT1 and SIRT3 at the enzyme level (fluorometrically), and NAD+ levels were measured spectrophotometrically. Results: We observed a reduction of SIRT1 and SIRT4 at the protein level, a downregulation of SIRT1 at the transcript level and increased NAD+ levels under hypoxia. SIRT3 was not affected by hypoxia. Conclusions: Downregulation of SIRT1 under hypoxia might reduce production of the reactive oxygen species (ROS) via the respiratory chain and inhibit the mitochondrial ATP-synthase, resulting in energy conservation. NOS might be impaired if SIRT1 is decreased. Increased NAD+ levels might compensate these effects. Hypoxic downregulation of SIRT4 might lead to mitochondrial uncoupling, hence endothelial dysfunction, and ADP/ATP-translocase 2 (ANT2)-inhibition. NAD+ upregulation might partly compensate this effect.

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Section: Discussionmentioning

confidence: 99%

“…In recent years, sirtuins (SIRTs) were shown to regulate vascular and especially endothelial functions under physiological conditions [1][2][3][4].…”

Section: Introductionmentioning

confidence: 99%

Impact of Short-Term Hypoxia on Sirtuins as Regulatory Elements in HUVECs

Pecher

Potthast

Versen‐Höynck

2020

JCM

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“…Rodents and humans demonstrate the critical role of SIRT3 in metabolic diseases, highlighting the decrease in SIRT3 activity in several tissues such as the liver, the adipose tissue and the muscle [174,175]. Mice deficient for SIRT3 on an HFD also reveal accelerated hallmarks of MetS [176].…”

Section: Ampk and Sirtuinsmentioning

confidence: 99%

Critical Role for AMPK in Metabolic Disease-Induced Chronic Kidney Disease

Juszczak

Caron

Mathew

et al. 2020

IJMS

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Chronic kidney disease (CKD) is prevalent in 9.1% of the global population and is a significant public health problem associated with increased morbidity and mortality. CKD is associated with highly prevalent physiological and metabolic disturbances such as hypertension, obesity, insulin resistance, cardiovascular disease, and aging, which are also risk factors for CKD pathogenesis and progression. Podocytes and proximal tubular cells of the kidney strongly express AMP-activated protein kinase (AMPK). AMPK plays essential roles in glucose and lipid metabolism, cell survival, growth, and inflammation. Thus, metabolic disease-induced renal diseases like obesity-related and diabetic chronic kidney disease demonstrate dysregulated AMPK in the kidney. Activating AMPK ameliorates the pathological and phenotypical features of both diseases. As a metabolic sensor, AMPK regulates active tubular transport and helps renal cells to survive low energy states. AMPK also exerts a key role in mitochondrial homeostasis and is known to regulate autophagy in mammalian cells. While the nutrient-sensing role of AMPK is critical in determining the fate of renal cells, the role of AMPK in kidney autophagy and mitochondrial quality control leading to pathology in metabolic disease-related CKD is not very clear and needs further investigation. This review highlights the crucial role of AMPK in renal cell dysfunction associated with metabolic diseases and aims to expand therapeutic strategies by understanding the molecular and cellular processes underlying CKD.

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“…SIRT3 has been shown to blockade cardiac hypertrophy and attenuate aging and oxidative stress-mediated cell death in cardiomyocytes via Foxo3a and Ku70 (24). In addition, SIRT3 deficiency impairs mitochondrial function and cardiac function by hyperacetylation of energy metabolic proteins and myocardial energy depletion (16, 17).…”

Section: Introductionmentioning

confidence: 99%

Microvascular Rarefaction and Heart Failure With Preserved Ejection Fraction

Zeng

Chen

2019

Front. Cardiovasc. Med.

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Heart failure with preserved ejection fraction (HFpEF) is characterized by diastolic dysfunction and is commonly seen in the elderly and diabetic and hypertensive patients. Despite its rising prevalence, the pathophysiology of HFpEF is poorly understood and its optimal treatment remains undefined. Recent clinical studies indicate that coronary microvascular rarefaction (reduced myocardial capillary density) with reduced coronary flow reserve (CFR) is a major contributor to diastolic dysfunction in HFpEF patients. On a molecular level, endothelial cells (EC) are dependent on glycolysis for supporting their functions and vascular homeostasis. Sirtuin 3 (SIRT3) has a critical role in the regulation of endothelial glycolytic metabolism and thus affects angiogenesis. Disruption of SIRT3-mediated EC metabolism and impairment of angiogenesis may promote cardiomyocyte hypoxia and myocardial fibrosis, leading to diastolic dysfunction and HFpEF. This review summarizes current knowledge of SIRT3 in EC metabolism, coronary microvascular rarefaction and HFpEF.

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Emerging role of SIRT3 in endothelial metabolism, angiogenesis, and cardiovascular disease

Cited by 85 publications

References 147 publications

Impact of Short-Term Hypoxia on Sirtuins as Regulatory Elements in HUVECs

Impact of Short-Term Hypoxia on Sirtuins as Regulatory Elements in HUVECs

Critical Role for AMPK in Metabolic Disease-Induced Chronic Kidney Disease

Microvascular Rarefaction and Heart Failure With Preserved Ejection Fraction

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