Losartan Protects the Heart Against Ischemia Reperfusion Injury: Sirtuin3 Involvement

Abstract

-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 realtime RT-PCR. Arrhythmias were assessed according to the Lambeth conventions.

Roles of SIRT3 in heart failure: from bench to bedside

“…Losartan is an angiotensin II type I receptor blocker that was introduced as an antihypotension medicine. Klishadi et al (2015) demonstrated that it exerted protective effects in ischemia reperfusion injuries by normalizing the protein level of SIRT3 and up-regulating the pro-survival factors in ischemic heart. Recently, another molecular Adjudin, which was developed as an anti-spermatogenic agent, was proved to directly activate mitochondrial-located SIRT3 in hair cells of the cochlea (Xia and Geng, 2016).…”

Effects of berberine on the pharmacokinetics of losartan and its metabolite EXP3174 in rats and its mechanism

“…Losartan is the first nonpeptide angiotensin II receptor blocker used for the treatment of hypertension (Klishadi et al 2015). After oral administration, losartan can be absorbed quickly and transformed in to its active metabolite EXP3174 mediated by cytochrome P450 enzymes CYP3A4 and CYP2C9, which is about 10-fold more potent than its parent drug (Rincon et al 2015).…”

The Role of SIRT3 in Mediating Cardioprotective Effects of RAS Inhibition on Cardiac Ischemia-Reperfusion

“…Although blockade of AT1 receptors improves post-ischemic recovery, prevents arrhythmia, increases Ca 2+ storage in the sarcoplasmic reticulum, reduces ROS, and attenuates mitochondrial dysfunction, a cause-effect relationship between these effects has not been established. The article by Klishadi and co-authors published in the Journal of Pharmacy and Pharmaceutical Sciences (10) attempts to establish a role for SIRT3 in the cardioprotective action of losartan following IR injury. The authors demonstrated that pre-treatment of rats with losartan (10 mg/kg/day) for 4 weeks significantly improved the recovery of hearts after in vivo IR induced by coronary artery ligation (30 min) and subsequent reperfusion (120 min).…”

“…They found that electrical heart abnormalities (ventricular tachycardia and ectopic beats) after IR were attenuated by losartan, a finding that was associated with increased SIRT3 protein levels. The authors concluded that chronic administration of losartan at non-hypotensive levels, could exert cardioprotection in part, through normalization the SIRT3 protein level in the ischemic myocardium (10). However, the involvement and role of mitochondrial SIRT3 in these cardioprotective effects of losartan were not considered, limiting the interpretation of the data.…”

“…Its expression decreases with age, and neurodegenerative, cardiovascular and metabolic diseases. The study by Klishadi et al (10) did not evaluate mitochondrial function and/or acetylation of mitochondrial proteins in losartan-pretreated versus untreated rats subjected to IR. Also, lack of data on the enzymatic activity of SIRT3 in mitochondria obscures the contribution of SIRT3 to losartan-induced cardioprotection in the ischemic myocardium.…”