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Sirtuin 1 Activator SRT1720 Protects against Organ Injury Induced by Intestinal Ischemia-Reperfusion #MMPMID26263437
Hansen LW; Khader A; Yang WL; Prince JM; Nicastro JM; Coppa GF; Wang P
Shock 2016[Apr]; 45 (4): 359-66 PMID26263437show ga
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. Maintenance of mitochondrial biogenesis is essential for cell survival, and is regulated in part by sirtuin 1, an energy-sensing enzyme. We hypothesized that sirtuin 1 activation with SRT1720 would reduce local and remote organ injury after intestinal I/R. Intestinal I/R was induced by 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. SRT1720 treatment of I/R mice resulted in a 57% increase in protein levels of succinate dehydrogenase (SDH), an index of mitochondrial mass, and a 120% increase in mRNA levels of mitochondrial transcription factor A (TFAM), 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 mRNA levels of TNF-? by 60% and inducible nitric oxide synthase (iNOS) to baseline after I/R. Systemic inflammation, as determined by serum IL-6, was reduced in treated mice. Lung injury, as measured by histologic architecture and myeloperoxidase activity, and lung apoptosis were also improved after 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 sirtuin 1-mediated pathway is a promising target for treatment of intestinal I/R injury.