Combined Therapy with SS31 and Mitochondria Mitigates Myocardial Ischemia-Reperfusion Injury in Rats.

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.

• Authors: Fan-Yen Lee, Pei-Lin Shao, Christopher Glenn Wallace, Sarah Chua, Pei-Hsun Sung, Sheung-Fat Ko, Han-Tan Chai, Sheng-Ying Chung, Kuan-Hung Chen, Hung-I Lu, Yi-Ling Chen, Tien-Hung Huang, Jiunn-Jye Sheu, Hon-Kan Yip
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 19 Issue 9 (Sep 15 2018) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 30223594 (Publication Type: Journal Article)

Chemical References

• Biomarkers
• Inflammation Mediators
• Oligopeptides
• arginyl-2,'6'-dimethyltyrosyl-lysyl-phenylalaninamide
• Adenosine Triphosphate
• Collagen
• Sirtuin 1

Topics

• Adenosine Triphosphate (metabolism)
• Animals
• Apoptosis (drug effects)
• Biomarkers (metabolism)
• Cell Line
• Collagen (metabolism)
• DNA Copy Number Variations
• DNA Damage (drug effects)
• Disease Models, Animal
• Echocardiography
• Inflammation Mediators (metabolism)
• Male
• Mitochondria (drug effects, genetics, metabolism)
• Myocardial Reperfusion Injury (diagnosis, drug therapy, metabolism)
• Myocardium (metabolism)
• Oligopeptides (pharmacology)
• Oxidative Stress (drug effects)
• Oxygen Consumption
• Rats
• Sirtuin 1 (metabolism)