Combined Therapy with SS31 and Mitochondria Mitigates Myocardial Ischemia-Reperfusion Injury in Rats
AbstractMyocardial 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. View Full-Text
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Lee, F.-Y.; Shao, P.-L.; Wallace, C.G.; Chua, S.; Sung, P.-H.; Ko, S.-F.; Chai, H.-T.; Chung, S.-Y.; Chen, K.-H.; Lu, H.-I.; Chen, Y.-L.; Huang, T.-H.; Sheu, J.-J.; Yip, H.-K. Combined Therapy with SS31 and Mitochondria Mitigates Myocardial Ischemia-Reperfusion Injury in Rats. Int. J. Mol. Sci. 2018, 19, 2782.
Lee F-Y, Shao P-L, Wallace CG, Chua S, Sung P-H, Ko S-F, Chai H-T, Chung S-Y, Chen K-H, Lu H-I, Chen Y-L, Huang T-H, Sheu J-J, Yip H-K. Combined Therapy with SS31 and Mitochondria Mitigates Myocardial Ischemia-Reperfusion Injury in Rats. International Journal of Molecular Sciences. 2018; 19(9):2782.Chicago/Turabian Style
Lee, Fan-Yen; Shao, Pei-Lin; Wallace, Christopher G.; Chua, Sarah; Sung, Pei-Hsun; Ko, Sheung-Fat; Chai, Han-Tan; Chung, Sheng-Ying; Chen, Kuan-Hung; Lu, Hung-I; Chen, Yi-Ling; Huang, Tien-Hung; Sheu, Jiunn-Jye; Yip, Hon-Kan. 2018. "Combined Therapy with SS31 and Mitochondria Mitigates Myocardial Ischemia-Reperfusion Injury in Rats." Int. J. Mol. Sci. 19, no. 9: 2782.
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