Impaired SIRT1 nucleocytoplasmic shuttling in the senescent heart during ischemic stress

Abstract

A "longevity " gene, sirtuin 1 (SIRT1), can attenuate age-dependent induction of left ventricular dysfunction. This study aimed to characterize the role of SIRT1 in the tolerance of aged heart to ischemic insults. Male C57BL/6 young (4-6 mo) and aged (24-26 mo) mice were used to determine the role of SIRT1 in myocardial ischemia/reperfusion (I/R) tolerance. SIRT1 localization was assessed by confocal microscopy. Immunoblotting was used to evaluate SIRT1 expression and translocation. The results demonstrated that SIRT1 is expressed predominantly as a sumoylated form in cardiomyocyte nuclei. Moreover, cardiac overexpression of desumoylase, sentrin-specific protease 2 (SENP2), significantly reduces nuclear sumoylated SIRT1 levels (P<0.05). Interestingly, I/R stress leads to desumoylation and translocation of nuclear SIRT1 into the cytoplasm in aged but not in young hearts. SIRT1 activity in ischemic young hearts was 3.2-fold higher than that seen in ischemic aged hearts, which suggests that aging causes impaired nucleocytoplasmic shuttling and activation of SIRT1 during ischemic stress. The infarct size in aged and Sirt1(+/-) knockout hearts was higher than that observed in young and Sirt1(+/+) WT littermate hearts, respectively (all P<0.05). SIRT1 agonist, SRT1720, reduced myocardial infarction in both aged and Sirt1(+/-) hearts. Therefore, impaired cardiac SIRT1 activity plays a critical role in the observed increase in susceptibility of the aged heart to I/R injury. SIRT1 agonist can restore this aging-related loss of cardioprotection.

The Ubiquitin-Like SUMO System and Heart Function

“…In the aging heart, nuclear translocation of SIRT1 is impaired during ischemic stress, hindering adaptive responses. 163 SUMOylation of SIRT1 increases its deacetylase activity, which is essential for adapting to genotoxic stress. 102 At present, it is not known whether SUMOylation regulates the nuclear versus cytoplasmic localization of SIRT1 or increases the activity of SIRT1 by other means.…”

Humulus japonicus extract exhibits antioxidative and anti-aging effects via modulation of the AMPK-SIRT1 pathway

“…In addition, a decrease in nuclear SIRT1 levels has been previously reported in the hearts of aged mice (27,28). Therefore, in the present study, nuclear proteins were employed for the detection of SIRT1.…”

Macromolecular crowding effect is critical for maintaining SIRT1's nuclear localization in cancer cells

“…The nucleocytoplasmic translocation of SIRT1 occurs under various physiological and pathological conditions, [6][7][8][9][10] however, the underlying mechanisms are poorly understood. The apoptosis-induced cytoplasmic localization of SIRT1 can be were fractionated by Digitonin-Ficoll approach (with 2 digitonin concentrations) followed by western blot analysis.…”

“…11 Caspase-mediated cleavage and sumoylation have also been shown to affect SIRT1 subcellular localization in different cells. 10,12 Since the identification of p53 as a SIRT1 deacetylating substrate, 13 the cancer-related roles of SIRT1 have been extensively investigated. Cumulative evidence suggests that SIRT1 could promote both tumor-suppressive and oncogenic activities and such bipolar functions of SIRT1 in tumorigenesis could be achieved by deacetylating different substrates with different subcellular localization.…”