Mitochondria-targeted combination treatment strategy counteracts myocardial reperfusion injury of aged rats by modulating autophagy and inflammatory response

Abstract

Background: Aging, as a recognized risk factor for ischemic heart disease, interferes with protective mechanisms and abolishes the optimal effectiveness of cardioprotective interventions, leading to the loss of cardioprotection following myocardial ischemia/reperfusion (I/R) injury. This study was designed to explore the possible interaction of aging with cardioprotection induced by combination therapy with coenzyme Q₁₀ (CoQ₁₀) and mitochondrial transplantation in myocardial I/R injury of aged rats.

Methods: Male Wistar rats (n = 72, 400-450 g, 22-24 months old) were randomized into groups with/without I/R and/or CoQ₁₀ and mitochondrial transplantation, alone or in a combinational mode. An in vivo model of myocardial I/R injury was established by left anterior descending coronary artery occlusion and re-opening. Mitochondria were isolated from donor rats and injected intramyocardially (150 µl of the mitochondrial suspension containing 2 × 10⁵±0.3 × 10⁵ mitochondria) at the onset of reperfusion in recipient groups. CoQ₁₀ (20 mg/kg/day) was injected intramuscularly for 7 days before I/R operation. Lastly, myocardial function, cTn-I level, expression of autophagy-associated proteins (Beclin1, p62, and LC3-II/LC3-I), and the levels of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) were assessed.

Results: Co-application of CoQ₁₀ and mitotherapy concomitantly improved myocardial function and decreased cTn-I level in aged reperfused hearts (P < .001). This combination therapy also modulated autophagic activity and decreased pro-inflammatory cytokines (P < .01 to P < .001). This combinational approach induced noticeable cardioprotection in comparison with monotherapies-received groups.

Conclusion: We found that combination of CoQ₁₀ and mitochondrial transplantation attenuated myocardial I/R injury in aged rats, in part by modulating autophagy and inflammatory response, hence, appears to restore aging-related loss of cardioprotection in aged patients.

Keywords: Aging; Autophagy; Inflammation; Myocardial infarction; Reperfusion injury..