SIRT1 Antagonizes Oxidative Stress in Diabetic Vascular Complication

Abstract

Diabetic mellitus (DM) is a significant public health concern worldwide with an increased incidence of morbidity and mortality, which is particularly due to the diabetic vascular complications. Several pivotal underlying mechanisms are associated with vascular complications, including hyperglycemia, mitochondrial dysfunction, inflammation, and most importantly, oxidative stress. Oxidative stress triggers defective angiogenesis, activates pro-inflammatory pathways and causes long-lasting epigenetic changes to facilitate the development of vascular complications. Therefore, therapeutic interventions targeting oxidative stress are promising to manage diabetic vascular complications. Sirtuin1 (SIRT1), a class III histone deacetylase belonging to the sirtuin family, plays critical roles in regulating metabolism and ageing-related pathological conditions, such as vascular diseases. Growing evidence has indicated that SIRT1 acts as a sensing regulator in response to oxidative stress and attenuates vascular dysfunction via cooperating with adenosine-monophosphate-activated protein kinase (AMPK) to activate antioxidant signals through various downstream effectors, including peroxisome proliferator-activated receptor-gamma co-activator 1 (PGC-1α), forkhead transcription factors (FOXOs), and peroxisome proliferative-activated receptor α (PPARα). In addition, SIRT1 interacts with hydrogen sulfide (H2S), regulates NADPH oxidase, endothelial NO synthase, and mechanistic target of rapamycin (mTOR) to suppress oxidative stress. Furthermore, mRNA expression of sirt1 is affected by microRNAs in DM. In the current review, we summarize recent advances illustrating the importance of SIRT1 in antagonizing oxidative stress. We also discuss whether modulation of SIRT1 can serve as a therapeutic strategy to treat diabetic vascular complications.

MICU3 regulates mitochondrial Ca2+-dependent antioxidant response in skeletal muscle aging

“…SIRT1 is a downstream effector of NAD + and plays an essential role in aging, apoptosis, and oxidative stress [ 34 – 36 ]. Our data show that SIRT1 might correlate with MICU3.…”

Lycium barbarum Extracts Extend Lifespan and Alleviate Proteotoxicity in Caenorhabditis elegans

“…As a protein deacetylase, SIRT1 can deacetylate transcriptional regulator hsf -1 ( 37 ) and also p53 ( 38 ), NF-κB ( 39 ), FOXOs ( 40 ), and PGC-1α ( 41 ). The downstream target genes of these transcription factors, such as HSP70, BDNF, CASP3, BCL2 , and SOD2 , are involved in a broad range of biological processes including protein quality control, cell survival, antioxidant, and antiinflammatory responses ( 42 , 43 ). Thus, it will be interesting to study whether LBE can enhance the activity of other transcription factors and downstream molecules through SIRT1 to rescue hsf-1 deficiency and extend lifespan.…”

Sirtuins: Potential Therapeutic Targets for Defense against Oxidative Stress in Spinal Cord Injury

“…According to the molecular analysis of the conserved core domain sequence of sirtuins from various organs and tissues, the seven members of the sirtuin family are divided into four groups: SIRT1, SIRT2, and SIRT3 as class I; SIRT4 as class II; SIRT5 as class III; and SIRT6 and SIRT7 as class IV [26]. Among them, SIRT1 is the most widely studied member of the sirtuin family, owing to its crucial role in many biological processes including oxidative stress response, cellular 3 Oxidative Medicine and Cellular Longevity metabolism, glucose homeostasis, and insulin secretion [26,78,79]. The human SIRT1 gene is on chromosome 10 and encodes a protein consisting of 746 amino acids that contains the NAD-binding catalytic core domain [76].…”