Related Experiment Video
Updated: Sep 1, 2025
Assessment of Human Adipose Tissue Microvascular Function Using Videomicroscopy
Published on: September 29, 2017
Targeting SIRT1 Rescues Age- and Obesity-Induced Microvascular Dysfunction in Ex Vivo Human Vessels
Alessandro Mengozzi1,2, Sarah Costantino3, Francesco Paneni3,4,5
1Department of Clinical and Experimental Medicine (A.M., E.D., M.N., I.P., L.A., M.F., C.I., N.B., N.R.P., S.T., A.V., S.M.), University of Pisa, Italy.
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/m2) and age (above or below 40 years) 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 (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. 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 p66Shc 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 p66Shc 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 p66Shc and Arginase II, it influences mtROS 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.
Insights
Silent information regulator 1 (SIRT1) plays a key role in preventing early microvascular damage from aging and obesity. Targeting SIRT1 therapeutically can restore endothelial function and prevent age- and obesity-related vascular issues.
Area of Science:
- Vascular Biology
- Aging Research
- Metabolic Syndrome
Background:
- Experimental evidence implicates silent information regulator 1 (SIRT1) in age- and metabolic-related vascular dysfunction.
- The role of SIRT1 in the human microvasculature, particularly in early-stage dysfunction, remains largely unknown.
- This study investigates SIRT1's role in the earliest microvascular changes associated with aging and obesity in humans.
Purpose of the Study:
- To investigate the role of silent information regulator 1 (SIRT1) in early human microvascular dysfunction.
- To determine if SIRT1 modulation can ameliorate age- and obesity-induced endothelial dysfunction.
- To explore the epigenetic mechanisms underlying SIRT1's influence on microvascular health.
Main Methods:
- Recruited 95 subjects stratified by age and BMI into four groups: Young Nonobese, Young Obese, Old Nonobese, and Old Obese.
- Assessed endothelial function using pressurized micromyography, measuring responses to a SIRT1 agonist (SRT1720) and a mitochondria reactive oxygen species (mtROS) scavenger (MitoTEMPO).
- Quantified vascular mtROS, nitric oxide (NO) availability, and gene expression of SIRT1 and mitochondrial proteins; investigated SIRT1-dependent epigenetic regulation via chromatin immunoprecipitation.
Main Results:
- Obese and older individuals exhibited lower vascular SIRT1 and antioxidant protein (FOXO3, SOD2) expression, alongside increased pro-oxidant proteins (p66Shc, Arginase II).
- Endothelial dysfunction in Old Obese, Young Obese, and Old Nonobese groups was significantly improved by SRT1720, comparable to MitoTEMPO treatment.
- SIRT1-dependent epigenetic changes reduced p66Shc and increased mitochondrial respiratory chain protein expression, explaining the functional improvements.
Conclusions:
- Silent information regulator 1 (SIRT1) is a critical regulator of early microvascular damage caused by aging and obesity.
- SIRT1 influences mtROS levels and NO availability through epigenetic control of p66Shc, Arginase II, and mitochondrial proteins.
- Therapeutic targeting of SIRT1 shows promise for preventing and treating age- and obesity-related microvascular dysfunction.
More Related Videos
08:22Combined Intravital Microscopy and Contrast-enhanced Ultrasonography of the Mouse Hindlimb to Study Insulin-induced Vasodilation and Muscle Perfusion
Published on: March 20, 2017
08:41Assessment of Vascular Tone Responsiveness using Isolated Mesenteric Arteries with a Focus on Modulation by Perivascular Adipose Tissues
Published on: June 3, 2019