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.

Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich’s ataxia cardiomyopathy model

“…Sirt3 ablation in the SIRT3-KO and dKO mice manifests in the development of cardiac concentric hypertrophy (Figure 2, G and H), consistent with the global SIRT3-KO literature (9, 10). We also found a role of SIRT3 for normal contractile function, which may explain the increased susceptibility to cardiac stressors in the global SIRT3-KO mouse (9)(10)(11). Given that global SIRT3-KO mice only show differences in cardiac function from WT controls upon cardiac stress (9)(10)(11), the findings that the FXN-KO and dKO mice showed no functional differences at baseline are consistent.…”

“…We also found a role of SIRT3 for normal contractile function, which may explain the increased susceptibility to cardiac stressors in the global SIRT3-KO mouse (9)(10)(11). Given that global SIRT3-KO mice only show differences in cardiac function from WT controls upon cardiac stress (9)(10)(11), the findings that the FXN-KO and dKO mice showed no functional differences at baseline are consistent. As such, we predict that cardiac induced-stress in the FXN-KO and dKO mice might reveal an exacerbated maladaptive response to the stress in the dKO model.…”

“…SIRT3 is required for both basal cardiac function and stress response. Studies investigating the role of SIRT3 in the heart have found enhanced age-induced cardiac hypertrophy (10) and increased susceptibility to cardiac stressors (9)(10)(11) in the absence of SIRT3, likely driven by marked reductions in cardiac ATP levels (12) and mitochondrial protein hyperacetylation (13). Recent work has identified that pathological cardiac remodeling and mitochondrial protein hyperacetylation are linked by redox imbalance (6).…”

Caloric restriction confers persistent anti-oxidative, pro-angiogenic, and anti-inflammatory effects and promotes anti-aging miRNA expression profile in cerebromicrovascular endothelial cells of aged rats

“…Despite recent advances in redox biology and aging research (9,21,27,33,37,49,51,52,55,59,65,72,97), the role of ROS in the cerebromicrovascular effects of CR remains elusive. To assess cellular peroxide production, we used the cell-permeant oxidative fluorescent indicator dye CM-H 2DCFDA [5 (and 6)-chloromethyl-2=,7=-dichlorodihydrofluorescein diacetateacetyl ester; Invitrogen, Carlsbad, CA] as we previously reported (16,86).…”

Sirtuins, aging, and cardiovascular risks

“…SIRT3 has been shown to block cardiac hypertrophy by reducing ROS synthesis from the mitochondria (Kim et al 2010). A recent study of Porter et al (2014) showed that under ischemic/reperfusion insult, at heart level, SIRT3 +/− adult and wild-type aged mice showed a similar phenotype of injury, resulting in a significant myocardial infarction area with respect to wild-type adult hearts. Moreover, the mitochondria isolated from wild-type aged heart possess a higher level of protein acetylation as observed in SIRT3 +/− hearts.…”