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

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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.

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The inflammatory response in myocardial infarction.

Nikolaos G Frangogiannis, C. Smith, Mark L. Entman (2002)

One of the major therapeutic goals of modern cardiology is to design strategies aimed at minimizing myocardial necrosis and optimizing cardiac repair following myocardial infarction. However, a sound understanding of the biology is necessary before a specific intervention is pursued on a therapeutic basis. This review summarizes our current understanding of the cellular and molecular mechanisms regulating the inflammatory response following myocardial ischemia and reperfusion. Myocardial necrosis induces complement activation and free radical generation, triggering a cytokine cascade initiated by Tumor Necrosis Factor (TNF)-alpha release. If reperfusion of the infarcted area is initiated, it is attended by an intense inflammatory reaction. Interleukin (IL)-8 synthesis and C5a activation have a crucial role in recruiting neutrophils in the ischemic and reperfused myocardium. Neutrophil infiltration is regulated through a complex sequence of molecular steps involving the selectins and the integrins, which mediate leukocyte rolling and adhesion to the endothelium. Marginated neutrophils exert potent cytotoxic effects through the release of proteolytic enzymes and the adhesion with Intercellular Adhesion Molecule (ICAM)-1 expressing cardiomyocytes. Despite this potential injury, substantial evidence suggests that reperfusion enhances cardiac repair improving patient survival; this effect may be in part related to the inflammatory response. Monocyte Chemoattractant Protein (MCP)-1 is also markedly upregulated in the infarcted myocardium inducing recruitment of mononuclear cells in the injured areas. Monocyte-derived macrophages and mast cells may produce cytokines and growth factors necessary for fibroblast proliferation and neovascularization, leading to effective repair and scar formation. At this stage expression of inhibitory cytokines such as IL-10 may have a role in suppressing the acute inflammatory response and in regulating extracellular matrix metabolism. Fibroblasts in the healing scar undergo phenotypic changes expressing smooth muscle cell markers. Our previous review in this journal focused almost exclusively on reduction of the inflammatory injury. The current update is prompted by the potential therapeutic opportunity that the open vessel offers. By promoting more effective tissue repair, it may be possible to reduce the deleterious remodeling, that is the leading cause of heart failure and death. Elucidating the complex interactions and regulatory mechanisms responsible for cardiac repair may allow us to design effective inflammation-related interventions for the treatment of myocardial infarction.

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Ischemia/Reperfusion.

Theodore Kalogeris, Christopher P. Baines, Maike Krenz … (2016)

Ischemic disorders, such as myocardial infarction, stroke, and peripheral vascular disease, are the most common causes of debilitating disease and death in westernized cultures. The extent of tissue injury relates directly to the extent of blood flow reduction and to the length of the ischemic period, which influence the levels to which cellular ATP and intracellular pH are reduced. By impairing ATPase-dependent ion transport, ischemia causes intracellular and mitochondrial calcium levels to increase (calcium overload). Cell volume regulatory mechanisms are also disrupted by the lack of ATP, which can induce lysis of organelle and plasma membranes. Reperfusion, although required to salvage oxygen-starved tissues, produces paradoxical tissue responses that fuel the production of reactive oxygen species (oxygen paradox), sequestration of proinflammatory immunocytes in ischemic tissues, endoplasmic reticulum stress, and development of postischemic capillary no-reflow, which amplify tissue injury. These pathologic events culminate in opening of mitochondrial permeability transition pores as a common end-effector of ischemia/reperfusion (I/R)-induced cell lysis and death. Emerging concepts include the influence of the intestinal microbiome, fetal programming, epigenetic changes, and microparticles in the pathogenesis of I/R. The overall goal of this review is to describe these and other mechanisms that contribute to I/R injury. Because so many different deleterious events participate in I/R, it is clear that therapeutic approaches will be effective only when multiple pathologic processes are targeted. In addition, the translational significance of I/R research will be enhanced by much wider use of animal models that incorporate the complicating effects of risk factors for cardiovascular disease. © 2017 American Physiological Society. Compr Physiol 7:113-170, 2017.

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Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury.

Kesheng Zhao, Guo-Min Zhao, Dunli Wu … (2004)

Reactive oxygen species (ROS) play a key role in promoting mitochondrial cytochrome c release and induction of apoptosis. ROS induce dissociation of cytochrome c from cardiolipin on the inner mitochondrial membrane (IMM), and cytochrome c may then be released via mitochondrial permeability transition (MPT)-dependent or MPT-independent mechanisms. We have developed peptide antioxidants that target the IMM, and we used them to investigate the role of ROS and MPT in cell death caused by t-butylhydroperoxide (tBHP) and 3-nitropropionic acid (3NP). The structural motif of these peptides centers on alternating aromatic and basic amino acid residues, with dimethyltyrosine providing scavenging properties. These peptide antioxidants are cell-permeable and concentrate 1000-fold in the IMM. They potently reduced intracellular ROS and cell death caused by tBHP in neuronal N(2)A cells (EC(50) in nm range). They also decreased mitochondrial ROS production, inhibited MPT and swelling, and prevented cytochrome c release induced by Ca(2+) in isolated mitochondria. In addition, they inhibited 3NP-induced MPT in isolated mitochondria and prevented mitochondrial depolarization in cells treated with 3NP. ROS and MPT have been implicated in myocardial stunning associated with reperfusion in ischemic hearts, and these peptide antioxidants potently improved contractile force in an ex vivo heart model. It is noteworthy that peptide analogs without dimethyltyrosine did not inhibit mitochondrial ROS generation or swelling and failed to prevent myocardial stunning. These results clearly demonstrate that overproduction of ROS underlies the cellular toxicity of tBHP and 3NP, and ROS mediate cytochrome c release via MPT. These IMM-targeted antioxidants may be very beneficial in the treatment of aging and diseases associated with oxidative stress.

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Author and article information

Journal

Journal ID (nlm-ta): Int J Mol Sci

Journal ID (iso-abbrev): Int J Mol Sci

Journal ID (publisher-id): ijms

Title: International Journal of Molecular Sciences

Publisher: MDPI

ISSN (Electronic): 1422-0067

Publication date (Electronic): 15 September 2018

Publication date Collection: September 2018

Volume: 19

Issue: 9

Electronic Location Identifier: 2782

Affiliations

[1 ]Division of Thoracic and Cardiovascular Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; fanyenlee2015@ 123456gmail.com (F.-Y.L.); luhung@ 123456adm.cgmh.org.tw (H.-I.L.)

[2 ]Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan

[3 ]Department of Nursing, Asia University, Taichung 41354, Taiwan; m8951016@ 123456gmail.com

[4 ]Department of Plastic Surgery, University Hospital of South Manchester, Manchester M23 9LT, UK; c.g.wallace@ 123456gmail.com

[5 ]Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; chuasr409@ 123456hotmail.com (S.C.); e12281@ 123456cgmh.org.tw (P.-H.S.); chaiht@ 123456mail.cgmh.org.tw (H.-T.C.); miosheny@ 123456gmail.com (S.-Y.C.); rylchen.msu@ 123456gmail.com (Y.-L.C.); tienhunghuang@ 123456gmail.com (T.-H.H.)

[6 ]Department of Radiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; sfatko@ 123456adm.cgmh.org.tw

[7 ]Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; amigofx35@ 123456gmail.com

[8 ]Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan

[9 ]Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan

[10 ]Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan

Author notes

[* ]Correspondence: cvsjjs@ 123456gmail.com (J.-J.S.); han.gung@ 123456msa.hinet.net (H.-K.Y.)

Author information

Kuan-Hung Chen https://orcid.org/0000-0002-2527-2825

Article

Publisher ID: ijms-19-02782

DOI: 10.3390/ijms19092782

PMC ID: 6164143

PubMed ID: 30223594

SO-VID: d5dd794f-d6a2-40f7-aaa8-65ea20f05bd2

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

History

Date received : 23 July 2018

Date accepted : 13 September 2018

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

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Most cited references 34

The inflammatory response in myocardial infarction.

Ischemia/Reperfusion.

Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury.

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