title: SIRT3 deficiency exacerbates ischemia-reperfusion injury: implication for aged hearts.
abstract: Ischemia-reperfusion (IR) injury is significantly worse in aged hearts, but the underlying mechanisms are poorly understood. Age-related damage to mitochondria may be a critical feature, which manifests in an exacerbation of IR injury. Silent information regulator of transcription 3 (SIRT3), the major mitochondrial NAD(+)-dependent lysine deacetylase, regulates a variety of functions, and its inhibition may disrupt mitochondrial function to impact recovery from IR injury. In this study, the role of SIRT3 in mediating the response to cardiac IR injury was examined using an in vitro model of SIRT3 knockdown (SIRT3(kd)) in H9c2 cardiac-derived cells and in Langendorff preparations from adult (7 mo old) wild-type (WT) and SIRT3(+/-) hearts and aged (18 mo old) WT hearts. SIRT3(kd) cells were more vulnerable to simulated IR injury and exhibited a 46% decrease in mitochondrial complex I (Cx I) activity with low O2 consumption rates compared with controls. In the Langendorff model, SIRT3(+/-) adult hearts showed less functional recovery and greater infarct vs. WT, which recapitulates the in vitro results. In WT aged hearts, recovery from IR injury was similar to SIRT3(+/-) adult hearts. Mitochondrial protein acetylation was increased in both SIRT3(+/-) adult and WT aged hearts (relative to WT adult), suggesting similar activities of SIRT3. Also, enzymatic activities of two SIRT3 targets, Cx I and MnSOD, were similarly and significantly inhibited in SIRT3(+/-) adult and WT aged cardiac mitochondria. In conclusion, decreased SIRT3 may increase the susceptibility of cardiac-derived cells and adult hearts to IR injury and may contribute to a greater level of IR injury in the aged heart.
authors.affiliation: Department of Pediatrics, University of Rochester Medical Center, Rochester, New York; and.
authors.forename: George A
authors.initials: GA
authors.lastname: Porter
authors.affiliation: Department of Anesthesiology, University of Rochester Medical Center, Rochester, New York.
authors.forename: William R
authors.initials: WR
authors.lastname: Urciuoli
authors.affiliation: Department of Anesthesiology, University of Rochester Medical Center, Rochester, New York.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Brookes
authors.affiliation: Department of Anesthesiology, University of Rochester Medical Center, Rochester, New York Sergiy_Nadtochiy@urmc.rochester.edu.
authors.forename: Sergiy M
authors.initials: SM
authors.lastname: Nadtochiy
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D015536:Down-Regulation; D006339:Heart Rate; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015428:Myocardial Reperfusion Injury / Q000453:epidemiology* / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D012307:Risk Factors; D056566:Sirtuin 3 / Q000172:deficiency* / Q000235:genetics; D016277:Ventricular Function, Left
chemical_list: C525046:Sirt3 protein, mouse; D056566:Sirtuin 3
keywords: SIRT3; acetylation; aging; heart; ischemia; mitochondria; reperfusion
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