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Losartan protects the heart against ischemia reperfusion injury: sirtuin3 involvement
Mohsen Sharifi Klishadi1, Farideh Zarei, Seyyed Hassan Hejazian
1Department of Physiology, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
Purpose:
Sirtuin-3 (SIRT3) deacetylase protects the heart against oxidative stress via survival factors upregulation. Clinical and experimental studies have demonstrated that activation of systemic and local renin-angiotensin system (RAS) is implicated in ischemia-induced cardiac injury. However, the relation between RAS and SIRT3 in pathophysiology of myocardial ischemia reperfusion is unknown. In this study, the cardiac transcription and expression of SIRT3 levels was examined in response to ischemia reperfusion in untreated and losartan treated rats.
Methods:
Rats were divided into control group, losartan group (L), and ischemia reperfusion (IR) groups with (L+IR) or without losatran pretreatment. Some rats were included as sham-operated and saline groups. IR was induced by left anterior descending artery occlusion. SIRT3 protein levels were determined by Western blot technique. The genes expression was specified by real-time RT-PCR. Arrhythmias were assessed according to the Lambeth conventions.
Results:
In L+IR group a significant reduction was noted in the number of ventricular ectopic beats (VEBs) and episodes of ventricular tachycardia (VT) (VEBs: P<0.001; VT: P<0.01 vs. IR). In IR group, SIRT3 protein level was decreased in the ischemic tissue by 26.7±5.9% (P<0.01 vs. Control). However, in the non-ischemic tissue the changes of SIRT3 protein content were not significant. In L+IR group SIRT3 protein levels in the ischemic part of Left ventricle were significantly different from IR group (P<0.001). SIRT3 mRNA level did not change significantly among the experimental groups. Thioredoxin-1 and catalase transcription level was increased in L+IR group compared to IR group (P<0.01).
Conclusion:
A decreased SIRT3 protein levels subsequent to IR might be a novel signaling mechanism involved in IR injury. Losartan at non-hypotensive dose exerts anti-ischemic effects in part by normalizing the SIRT3 protein level and upregulating the survival factors encoding genes transcription in ischemic tissue of the heart.
Insights
Losartan treatment normalized heart Sirtuin-3 (SIRT3) protein levels and reduced arrhythmias following ischemia reperfusion injury. This suggests SIRT3 plays a role in myocardial protection and that losartan may offer therapeutic benefits.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Biochemistry
Background:
- Sirtuin-3 (SIRT3) is a deacetylase that protects the heart from oxidative stress by upregulating survival factors.
- The renin-angiotensin system (RAS) is known to contribute to cardiac injury during ischemia.
- The interplay between RAS and SIRT3 in myocardial ischemia reperfusion (IR) injury remains unclear.
Purpose of the Study:
- To investigate the relationship between the renin-angiotensin system (RAS) and Sirtuin-3 (SIRT3) in the context of myocardial ischemia reperfusion (IR) injury.
- To examine the effects of losartan, an angiotensin receptor blocker, on cardiac SIRT3 expression and IR injury in rats.
Main Methods:
- Rats were subjected to ischemia reperfusion (IR) injury, with some pretreated with losartan.
- SIRT3 protein levels were quantified using Western blot.
- Gene expression of SIRT3, thioredoxin-1, and catalase was analyzed via real-time RT-PCR.
- Arrhythmias were assessed using established conventions.
Main Results:
- Ischemia reperfusion (IR) significantly decreased SIRT3 protein levels in the ischemic cardiac tissue.
- Losartan pretreatment significantly reduced ventricular ectopic beats and ventricular tachycardia episodes compared to IR alone.
- Losartan treatment normalized SIRT3 protein levels in the ischemic myocardium and increased transcription of thioredoxin-1 and catalase.
- SIRT3 mRNA levels did not show significant changes across experimental groups.
Conclusions:
- Reduced SIRT3 protein levels following ischemia reperfusion (IR) may represent a key signaling mechanism in IR-induced cardiac injury.
- Losartan, at non-hypotensive doses, demonstrates anti-ischemic effects by restoring SIRT3 protein levels and upregulating survival factor gene transcription in the ischemic heart.
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