OBJECTIVE:Experimental evidence suggests a relevant role of SIRT1 in age- and metabolic-related vascular dysfunction. Whether these effects hold true in the human microvasculature is unknown. We aimed to investigate the role of SIRT1 in age- and obesity-related microvascular dysfunction in humans.
DESIGN AND METHOD:Individuals (n = 95) undergoing laparoscopic surgery were stratified by BMI status (above or below 30 Kg/m2) and age (above or below 40 years) and classified as young control (YC), young obese (YO), old control (OC) and old obese (OO). Endothelial function was assessed in small resistance arteries by pressurized micromyography, before and after incubation with a SIRT1 agonist (SRT1720) and a mitochondria reactive oxygen species (mtROS) scavenger (MitoTEMPO). We assessed vascular levels of mtROS and nitric oxide availability by confocal microscopy and vascular gene expression of SIRT1 and mitochondrial proteins by qPCR. ChIP assay was employed to investigate SIRT1-dependent epigenetic regulation of mitochondrial proteins.
RESULTS:Endothelial function showed a graded decrease from YC to OO, with reduced nitric oxide availability and increased mtROS levels. Similarly, SIRT1 and mitochondrial antioxidant proteins (FOXO3 and SOD2) expression levels were reduced while there was a higher expression of pro-oxidant and ageing mitochondria proteins p66Shc and Arginase II. OO, YO and OC endothelial function was rescued by SRT1720 (Figure). The improvement in endothelial function showed a linear relationship with age, BMI and vascular emodelling. The restoration was comparable to the one obtained with mitoTEMPO in the same groups. These effects were explained by SIRT1-dependent chromatin changes leading to reduced p66Shc expression and upregulation of proteins involved in mitochondria respiratory chain: ATP synthase 6, cytochrome B, NADH dehydrogenase 2, NADH dehydrogenase 5.
CONCLUSIONS:Restoring SIRT1 activity rescues obesity and age-related endothelial dysfunction. Its epigenetic control on mitochondrial pathways influences mtROS levels, NO availability, and the expression of the mitochondria respiratory chain proteins. SIRT1 is a novel central regulator of a homeostatic axis connecting vascular phenotype to systemic metabolism and ageing and to exposure to external adverse stimuli. Early targeting of SIRT1 might represent a crucial strategy to prevent the microvascular dysfunction related to age and obesity.