A novel mtDNA repair fusion protein attenuates maladaptive remodeling and preserves cardiac function in heart failure

作者：Bradley Jessica M; Li Zhen; Organ Chelsea L; Polhemus David J; Otsuka Hiroyuki; Islam Kazi N; Bhushan Shashi; Gorodnya Olena M; Ruchko Mykhaylo V; Gillespie Mark N; Wilson Glenn L; Lefer David J^*

来源：American Journal of Physiology - Heart and Circulatory Physiology, 2018, 314(2): H311-H321.

DOI：10.1152/ajpheart.00515.2017

• DNA repair
• hypertrophic cardiomyopathy
• mitochondria-targeted peptide
• mitochondrial injury
• myocardial infarction

Oxidative stress results in mtDNA damage and contributes to myocardial cell death. mtDNA repair enzymes are crucial for mtDNA repair and cell survival. We investigated a novel, mitochondria-targeted fusion protein (Exscien1-III) containing endonuclease III in myocardial ischemia-reperfusion injury and transverse aortic constriction (TAC)-induced heart failure. Male C57/BL6J mice (10-12 wk) were subjected to 45 min of myocardial ischemia and either 24 h or 4 wk of reperfusion. Exscien1-III (4 mg/kg ip) or vehicle was administered at the time of reperfusion. Male C57/BL6J mice were subjected to TAC, and Exscien1-III (4 mg/kg i.p) or vehicle was administered daily starting at 3 wk post-TAC and continued for 12 wk. Echocardiography was performed to assess left ventricular (LV) structure and function. Exscien1-III reduced myocardial infarct size (P < 0.01) at 24 h of reperfusion and preserved LV ejection fraction at 4 wk postmyocardial ischemia. Exscien1-III attenuated TAC-induced LV dilation and dysfunction at 6-12 wk post-TAC (P < 0.05). Exscien1-III reduced (P < 0.05) cardiac hypertrophy and maladaptive remodeling after TAC. Assessment of cardiac mitochondria showed that Exscien1-III localized to mitochondria and increased mitochondrial antioxidant and reduced apoptotic markers. In conclusion, our results indicate that administration of Exscien1-III provides significant protection against myocardial ischemia and preserves myocardial structure and LV performance in the setting of heart failure.
NEW & NOTEWORTHY Oxidative stress-induced mitochondrial DNA damage is a prominent feature in the pathogenesis of cardiovascular diseases. In the present study, we demonstrate the efficacy of a novel, mitochondria-targeted fusion protein that traffics endonuclease III specifically for mitochondrial DNA repair in two well-characterized murine models of cardiac injury and failure.

• 出版日期2018-2