Abstract
Myocardial ischemia-reperfusion (IR) injury contributes to adverse cardiac outcomes after myocardial ischemia, cardiac surgery, or circulatory arrest. In this study, we evaluated the ability of combined SS31-mitochondria (Mito) therapy to protect heart cells from myocardial IR injury. Adult male SD rats (n = 8/each group) were randomized: group 1 (sham-operated control), group 2 (IR, 30-min ischemia/72 h reperfusion), group 3 (IR-SS31 (2 mg intra-peritoneal injection at 30 min/24 h/48 h after IR)), group 4 (IR-mitochondria (2 mg/derived from donor liver/intra-venous administration/30 min after IR procedure)), and group 5 (IR-SS31-mitochondria). In H9C2 cells, SS31 suppressed menadione-induced oxidative-stress markers (NOX-1, NOX-2, oxidized protein) while it increased SIRT1/SIRT3 expression and ATP levels. In adult male rats 72 h after IR, left ventricular ejection fraction (LVEF) was highest in sham-operated control animals and lowest in the IR group. LVEF was also higher in IR rats treated with SS31-Mito than untreated IR rats or those treated with Mito or SS31 alone. Areas of fibrosis/collagen-deposition showed the opposite pattern. Likewise, levels of oxidative-stress markers (NOX-1, NOX-2, oxidized protein), inflammatory markers (MMP-9, CD11, IL-1β, TNF-α), apoptotic markers (mitochondrial-Bax, cleaved-caspase-3, PARP), fibrosis markers (p-Smad3, TGF-β), DNA-damage (γ-H2AX), sarcomere-length, and pressure/volume overload markers (BNP, β-MHC) all showed a pattern opposite that of LVEF. Conversely, anti-apoptotic (BMP-2, Smad1/5) and energy integrity (PGC-1α/mitochondrial cytochrome-C) markers exhibited a pattern identical to that of LVEF. This study demonstrates that the combined SS31-Mito therapy is superior to either therapy alone for protecting myocardium from IR injury and indicates that the responsible mechanisms involved increased SIRT1/SIRT3 expression, which suppresses inflammation and oxidative stress and protects mitochondrial integrity.
Highlights
Myocardial ischemia-reperfusion (IR), which is a pathological condition, is characterized by loss of the coronary blood supply to the myocardium followed by the restoration of perfusion as exemplified by acute myocardial infarction (AMI) during primary coronary intervention [1]
We evaluated the therapeutic potential of combined mitochondria replacement and SS31 treatment using a rodent model of acute myocardial IR injury
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Summary
Myocardial ischemia-reperfusion (IR), which is a pathological condition, is characterized by loss of the coronary blood supply to the myocardium followed by the restoration of perfusion as exemplified by acute myocardial infarction (AMI) during primary coronary intervention [1]. ROS plays a crucial role to turn on the mitochondrial permeability transition pore, which results in the release of mitochondrial cytochrome C and other elements that further lead to cellular hyper-contracture and death [14,15]. This leads to the loss of cardiac contractility and alterations in cardiovascular function [16,17]. An alternative safe and efficacious treatment modality needs to be found
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