SIRTUIN 1 ACTIVATOR SRT1720 PROTECTS AGAINST ORGAN INJURY INDUCED BY INTESTINAL ISCHEMIA-REPERFUSION.
Intestinal ischemia-reperfusion (I/R) occurs in various clinical situations and causes local and remote organ injury, especially in the lungs, leading to significant morbidity and mortality. The maintenance of mitochondrial biogenesis is essential for cell survival and is regulated in part by sirtuin 1 (SIRT1), an energy-sensing enzyme. We hypothesized that SIRT1 activation with SRT1720 would reduce local and remote organ injury after intestinal I/R. Intestinal I/R was induced by the occlusion of the superior mesenteric artery of adult male C57BL/6 mice for 45 min, followed by reperfusion for 4 h. SRT1720 or vehicle was injected intravenously at the time of reperfusion. Blood, small intestine, and lung tissues were collected for analysis. The SRT1720 treatment of I/R mice resulted in a 57% increase in protein levels of succinate dehydrogenase, an index of mitochondrial mass, and a 120% increase in messenger RNA levels of mitochondrial transcription factor A, a marker for mitochondrial biogenesis. The microscopic architecture and apoptosis of the gut tissue was improved in the SRT1720-treated I/R mice. SRT1720 decreased intestinal messenger RNA levels of tumor necrosis factor-α by 60% and inducible nitric oxide synthase to baseline after I/R. Systemic inflammation, as determined by serum interleukin-6, was reduced in treated mice. Lung injury, as measured by histological architecture and myeloperoxidase activity, and lung apoptosis were also improved after the SRT1720 treatment. SRT1720 preserved mitochondrial biogenesis and mass, leading to inhibition of inflammation and oxidative stress, thereby protecting against intestinal I/R-induced injury. Thus, the SIRT1-mediated pathway is a promising target for the treatment of intestinal I/R injury.
*Department of Surgery, Hofstra North Shore-Long Island Jewish School of Medicine †Center for Translational Research, The Feinstein Institute for Medical Research, Manhasset, New York.
Laura W
LW
Hansen
Adam
A
Khader
Weng-Lang
WL
Yang
Jose M
JM
Prince
Jeffrey M
JM
Nicastro
Gene F
GF
Coppa
Ping
P
Wang
D000818:Animals; D020536:Enzyme Activators / Q000494:pharmacology*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D007410:Intestinal Diseases / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D007422:Intestines / Q000098:blood supply / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D015427:Reperfusion Injury / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D056564:Sirtuin 1 / Q000378:metabolism*
D020536:Enzyme Activators; D006576:Heterocyclic Compounds, 4 or More Rings; C525422:SRT1720; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1