Abstract
Early myocardial reperfusion is an effective therapy but ischemia/reperfusion (I/R) causes lethal myocardial injury. The aging heart was reported to show greater cardiac damage after I/R injury than that observed in young hearts. Senescence marker protein 30 (SMP30), whose expression decreases with age, plays a role in reducing oxidative stress and apoptosis. However, the impact of SMP30 on myocardial I/R injury remains to be determined. In this study, the left anterior descending coronary artery was occluded for 30 min, followed by reperfusion in wild-type (WT) and SMP30 knockout (KO) mice. After I/R, cardiomyocyte apoptosis and the ratio of infarct area/area at risk were higher, left ventricular fractional shortening was lower, and reactive oxygen species (ROS) generation was enhanced in SMP30 KO mice. Moreover, the previously increased phosphorylation of GSK-3β and Akt was lower in SMP30 KO mice than in WT mice. In cardiomyocytes, silencing of SMP30 expression attenuated Akt and GSK-3β phosphorylation, and increased Bax to Bcl-2 ratio and cardiomyocyte apoptosis induced by hydrogen peroxide. These results suggested that SMP30 deficiency augments myocardial I/R injury through ROS generation and attenuation of Akt activation.
Highlights
Percutaneous coronary intervention has been reported to reduce the mortality in patients with acute coronary infarction, since coronary reperfusion therapy is the most effective treatment for salvaging viable myocardium [1,2]
There is no significant difference in the cardiac function between WT mice and Senescence marker protein 30 (SMP30) KO mice, ; we have recently reported that SMP30 plays a protective role in angiotensin II-induced cardiac hypertrophy and doxorubicin-induced cardiotoxicity in mice via anti-apoptosis and anti-oxidant effects [17,24,25]
The size of infarction area (IA)/area at risk (AAR) ratio was significantly higher in SMP30 KO than in WT mice (Figure 1A,B)
Summary
Percutaneous coronary intervention has been reported to reduce the mortality in patients with acute coronary infarction, since coronary reperfusion therapy is the most effective treatment for salvaging viable myocardium [1,2]. Previous studies have reported that abnormalities in mitochondrial function and calcium handling, excessive generation of oxidative stress, and attenuation of cardioprotective signaling are potentially implicated in the aging heart [14,15,16]. The precise mechanism by which cardiac senescence induces a loss of protective function against I/R injury is not fully understood. It has been reported that the expression of senescence marker protein 30 (SMP30) decreases with aging in an androgen-independent manner; this mechanism is observed in the heart [17,18]. There is no significant difference in the cardiac function between WT mice and SMP30 KO mice, ; we have recently reported that SMP30 plays a protective role in angiotensin II-induced cardiac hypertrophy and doxorubicin-induced cardiotoxicity in mice via anti-apoptosis and anti-oxidant effects [17,24,25]. We evaluated the mechanisms by which SMP30 deficiency exacerbates myocardial I/R injury
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