Sirtuin 1 as the mechanism of action of agents used in the diabetes mellitus pharmacotherapy

Stelmaszyk, Agnieszka; Mikołajczak, Przemysław Ł.; Dworacka, Marzena

doi:10.1016/j.ejphar.2021.174289

Cited by 8 publications

(8 citation statements)

References 54 publications

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“…Treatment of VSMC with garcinol, a PCAF inhibitor, significantly reduced ROS formation, suggesting that inhibition of hyperacetylation-induced PCAF may be a potential treatment to protect the vasculature and prevent long term cardiovascular complications in diabetics. Worldwide increasing T2DM prevalence demands improvements in drug design and targeting PTMs correlated with diabetic complications poses a promising approach for treating T2DM and its vascular complications (Frkic et al 2021 ; Stelmaszyk et al 2021 ). In summary, findings from this study suggest that in advanced T2DM, PCAF is upregulated leading to increased vascular lysine acetylation and subsequent ROS production in VSMC, resulting in VSMC-related impaired vasodilation in advanced T2DM (Fig.…”

Section: Discussionmentioning

confidence: 99%

Vascular hyperacetylation is associated with vascular smooth muscle dysfunction in a rat model of non-obese type 2 diabetes

Carrillo-Sepúlveda

Maddie

Johnson

et al. 2022

Mol Med

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Background Advanced type 2 diabetes mellitus (T2DM) accelerates vascular smooth muscle cell (VSMC) dysfunction which contributes to the development of vasculopathy, associated with the highest degree of morbidity of T2DM. Lysine acetylation, a post-translational modification (PTM), has been associated with metabolic diseases and its complications. Whether levels of global lysine acetylation are altered in vasculature from advanced T2DM remains undetermined. We hypothesized that VSMC undergoes dysregulation in advanced T2DM which is associated with vascular hyperacetylation. Methods Aged male Goto Kakizaki (GK) rats, a non-obese murine model of T2DM, and age-matched male Wistar rats (control group) were used in this study. Thoracic aortas were isolated and examined for measurement of global levels of lysine acetylation, and vascular reactivity studies were conducted using a wire myograph. Direct arterial blood pressure was assessed by carotid catheterization. Cultured human VSMCs were used to investigate whether lysine acetylation participates in high glucose-induced reactive oxygen species (ROS), a crucial factor triggering diabetic vascular dysfunction. Results The GK rats exhibited marked glucose intolerance as well as insulin resistance. Cardiovascular complications in GK rats were confirmed by elevated arterial blood pressure and reduced VSMC-dependent vasorelaxation. These complications were correlated with high levels of vascular global lysine acetylation. Human VSMC cultures incubated under high glucose conditions displayed elevated ROS levels and increased global lysine acetylation. Inhibition of hyperacetylation by garcinol, a lysine acetyltransferase and p300/CBP association factor (PCAF) inhibitor, reduced high glucose-induced ROS production in VSMC. Conclusion This study provides evidence that vascular hyperacetylation is associated with VSMC dysfunction in advanced T2DM. Understanding lysine acetylation regulation in blood vessels from diabetics may provide insight into the mechanisms of diabetic vascular dysfunction, and opportunities for novel therapeutic approaches to treat diabetic vascular complications.

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Section: Discussionmentioning

confidence: 99%

Vascular hyperacetylation is associated with vascular smooth muscle dysfunction in a rat model of non-obese type 2 diabetes

Carrillo-Sepúlveda

Maddie

Johnson

et al. 2022

Mol Med

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“…SIRT1 is a member of the histone III deacetylase family, responsible for the deacetylation of lysine in histones and the conservation of DNA in the state of transcriptionally inactive heterochromatin [ 89 ]. Additionally, sirtuin-1 causes deacetylation of many regulatory proteins and transcription factors, including NF-κB and peroxisome proliferator-activated receptor γ (PPARγ), forkhead box O1 (FoxO1) and enhances NO production by deacetylating eNOS [ 49 , 50 , 51 ].…”

Section: Mirnas and Their Specific Roles In Endothelial Cell Senescencementioning

confidence: 99%

The Role of MicroRNAs in Endothelial Cell Senescence

Nikolajević

Ariaee

Liew

et al. 2022

Cells

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Cellular senescence is a complex, dynamic process consisting of the irreversible arrest of growth and gradual deterioration of cellular function. Endothelial senescence affects the cell’s ability to repair itself, which is essential for maintaining vascular integrity and leads to the development of endothelial dysfunction, which has an important role in the pathogenesis of cardiovascular diseases. Senescent endothelial cells develop a particular, senescence-associated secretory phenotype (SASP) that detrimentally affects both surrounding and distant endothelial cells, thereby facilitating the ageing process and development of age-related disorders. Recent studies highlight the role of endothelial senescence and its dysfunction in the pathophysiology of several age-related diseases. MicroRNAs are small noncoding RNAs that have an important role in the regulation of gene expression at the posttranscriptional level. Recently, it has been discovered that miRNAs could importantly contribute to endothelial cell senescence. Overall, the research focus has been shifting to new potential mechanisms and targets to understand and prevent the structural and functional changes in ageing senescent endothelial cells in order to prevent the development and limit the progression of the wide spectrum of age-related diseases. The aim of this review is to provide some insight into the most important pathways involved in the modulation of endothelial senescence and to reveal the specific roles of several miRNAs involved in this complex process. Better understanding of miRNA’s role in endothelial senescence could lead to new approaches for prevention and possibly also for the treatment of endothelial cells ageing and associated age-related diseases.

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“…Specifically, during a fasting state, decreased insulin and increased glucagon stimulate gluconeogenesis. Increased caloric restriction causes a SIRT1-dependent decrease in glucose, increased catabolism of fatty acids, decreased cholesterol uptake into the intestine, and limited fatty liver disease and inflammation [ 25 ]. A link between FOXO, signal transducer and activator of transcription 3 (STAT3), and SIRT1 has been identified to regulate gluconeogenesis [ 26 ].…”

Section: Reviewmentioning

confidence: 99%

“…For example, research suggests that SIRT1 mediates metformin’s effects in suppressing hepatic gluconeogenesis, activating fatty acid oxidation, and preventing hyperglycemia-induced retinal damage [ 10 ]. Furthermore, metformin used with caloric restriction, such as intermittent fasting, increased the expression of SIRT1 and furthered these beneficial effects [ 25 ]. Incretin mimetics, also known as glucagon-like peptide-1 (GLP-1) agonists, and dipeptidyl peptidase-4 (DPP4) inhibitors are both common classes of drugs used in the treatment of diabetes.…”

Section: Reviewmentioning

confidence: 99%

“…Incretin mimetics, also known as glucagon-like peptide-1 (GLP-1) agonists, and dipeptidyl peptidase-4 (DPP4) inhibitors are both common classes of drugs used in the treatment of diabetes. Both stimulate pathways leading to upregulation of SIRT1 to limit oxidative stress and alleviate the progression of insulin resistance [ 25 ]. Sodium-glucose co-transporter 2 (SGLT2) inhibitors are another class of medications used in type 2 diabetes mellitus.…”

Section: Reviewmentioning

confidence: 99%

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Role of Sirtuins in Diabetes and Age-Related Processes

Lingappa¹,

Mayrovitz²

2022

Cureus

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The practice of intermittent fasting continues to grow as a widely practiced diet trend due to its feasibility and reported high success rate. By practicing intermittent fasting, levels of sirtuin proteins (SIRTs), also known as the longevity protein, rise in the body and bring numerous health benefits. Currently, seven SIRTs have been described in humans in different locations of the cell with a wide variety of corresponding functions including gene transcription, DNA repair, and protection against oxidative damage. SIRT activators, such as resveratrol found in red wine, are also commonly consumed to amplify the health benefits associated with protection against diabetes and age-related disease processes. The purpose of this review is to explore the interaction of intermittent fasting on SIRT levels and how the increase in these proteins impacts age-related disease processes. The understanding of SIRTs is continuously evolving as more interactions and SIRT-specific activators are being revealed. New discoveries are crucial for forming potential therapeutics that delay many common diseases and promote healthy living.

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Sirtuin 1 as the mechanism of action of agents used in the diabetes mellitus pharmacotherapy

Cited by 8 publications

References 54 publications

Vascular hyperacetylation is associated with vascular smooth muscle dysfunction in a rat model of non-obese type 2 diabetes

Vascular hyperacetylation is associated with vascular smooth muscle dysfunction in a rat model of non-obese type 2 diabetes

The Role of MicroRNAs in Endothelial Cell Senescence

Role of Sirtuins in Diabetes and Age-Related Processes

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