Targeting Mitochondrial Fission Using Mdivi-1 in A Clinically Relevant Large Animal Model of Acute Myocardial Infarction: A Pilot Study
<b>Background</b>: New treatments are needed to reduce myocardial infarct size (MI) and prevent heart failure (HF) following acute myocardial infarction (AMI), which are the leading causes of death and disability worldwide. Studies in rodent AMI models showed that genetic and pharmacolog...
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MDPI AG
2019-08-01
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Online Access: | https://www.mdpi.com/1422-0067/20/16/3972 |
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Article |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Sang-Bing Ong Xiu-Yi Kwek Khairunnisa Katwadi Sauri Hernandez-Resendiz Gustavo E. Crespo-Avilan Nur Izzah Ismail Ying-Hsi Lin En Ping Yap Song-Yi Lim K P Myu Mai Ja Chrishan J.A. Ramachandra Nicole Tee Jin Jiat Toh Winston Shim Philip Wong Hector A. Cabrera-Fuentes Derek J Hausenloy |
spellingShingle |
Sang-Bing Ong Xiu-Yi Kwek Khairunnisa Katwadi Sauri Hernandez-Resendiz Gustavo E. Crespo-Avilan Nur Izzah Ismail Ying-Hsi Lin En Ping Yap Song-Yi Lim K P Myu Mai Ja Chrishan J.A. Ramachandra Nicole Tee Jin Jiat Toh Winston Shim Philip Wong Hector A. Cabrera-Fuentes Derek J Hausenloy Targeting Mitochondrial Fission Using Mdivi-1 in A Clinically Relevant Large Animal Model of Acute Myocardial Infarction: A Pilot Study International Journal of Molecular Sciences mdivi-1 mitochondrial morphology cardioprotection Drp1 pig ischemia/reperfusion injury |
author_facet |
Sang-Bing Ong Xiu-Yi Kwek Khairunnisa Katwadi Sauri Hernandez-Resendiz Gustavo E. Crespo-Avilan Nur Izzah Ismail Ying-Hsi Lin En Ping Yap Song-Yi Lim K P Myu Mai Ja Chrishan J.A. Ramachandra Nicole Tee Jin Jiat Toh Winston Shim Philip Wong Hector A. Cabrera-Fuentes Derek J Hausenloy |
author_sort |
Sang-Bing Ong |
title |
Targeting Mitochondrial Fission Using Mdivi-1 in A Clinically Relevant Large Animal Model of Acute Myocardial Infarction: A Pilot Study |
title_short |
Targeting Mitochondrial Fission Using Mdivi-1 in A Clinically Relevant Large Animal Model of Acute Myocardial Infarction: A Pilot Study |
title_full |
Targeting Mitochondrial Fission Using Mdivi-1 in A Clinically Relevant Large Animal Model of Acute Myocardial Infarction: A Pilot Study |
title_fullStr |
Targeting Mitochondrial Fission Using Mdivi-1 in A Clinically Relevant Large Animal Model of Acute Myocardial Infarction: A Pilot Study |
title_full_unstemmed |
Targeting Mitochondrial Fission Using Mdivi-1 in A Clinically Relevant Large Animal Model of Acute Myocardial Infarction: A Pilot Study |
title_sort |
targeting mitochondrial fission using mdivi-1 in a clinically relevant large animal model of acute myocardial infarction: a pilot study |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1422-0067 |
publishDate |
2019-08-01 |
description |
<b>Background</b>: New treatments are needed to reduce myocardial infarct size (MI) and prevent heart failure (HF) following acute myocardial infarction (AMI), which are the leading causes of death and disability worldwide. Studies in rodent AMI models showed that genetic and pharmacological inhibition of mitochondrial fission, induced by acute ischemia and reperfusion, reduced MI size. Whether targeting mitochondrial fission at the onset of reperfusion is also cardioprotective in a clinically-relevant large animal AMI model remains to be determined. <b>Methods</b>: Adult pigs (30–40 kg) were subjected to closed-chest 90-min left anterior descending artery ischemia followed by 72 h of reperfusion and were randomized to receive an intracoronary bolus of either mdivi-1 (1.2 mg/kg, a small molecule inhibitor of the mitochondrial fission protein, Drp1) or vehicle control, 10-min prior to reperfusion. The left ventricular (LV) size and function were both assessed by transthoracic echocardiography prior to AMI and after 72 h of reperfusion. MI size and the area-at-risk (AAR) were determined using dual staining with Tetrazolium and Evans blue. Heart samples were collected for histological determination of fibrosis and for electron microscopic analysis of mitochondrial morphology. <b>Results</b>: A total of 14 pigs underwent the treatment protocols (eight control and six mdivi-1). Administration of mdivi-1 immediately prior to the onset of reperfusion did not reduce MI size (MI size as % of AAR: Control 49.2 ± 8.6 vs. mdivi-1 50.5 ± 11.4; p = 0.815) or preserve LV systolic function (LV ejection fraction %: Control 67.5 ± 0.4 vs. mdivi-1 59.6 ± 0.6; p = 0.420), when compared to vehicle control. Similarly, there were no differences in mitochondrial morphology or myocardial fibrosis between mdivi-1 and vehicle control groups. <b>Conclusion</b>: Our pilot study has shown that treatment with mdivi-1 (1.2 mg/kg) at the onset of reperfusion did not reduce MI size or preserve LV function in the clinically-relevant closed-chest pig AMI model. A larger study, testing different doses of mdivi-1 or using a more specific Drp1 inhibitor are required to confirm these findings. |
topic |
mdivi-1 mitochondrial morphology cardioprotection Drp1 pig ischemia/reperfusion injury |
url |
https://www.mdpi.com/1422-0067/20/16/3972 |
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doaj-85d666df8d694e5b99e833917f91af302020-11-25T01:15:29ZengMDPI AGInternational Journal of Molecular Sciences1422-00672019-08-012016397210.3390/ijms20163972ijms20163972Targeting Mitochondrial Fission Using Mdivi-1 in A Clinically Relevant Large Animal Model of Acute Myocardial Infarction: A Pilot StudySang-Bing Ong0Xiu-Yi Kwek1Khairunnisa Katwadi2Sauri Hernandez-Resendiz3Gustavo E. Crespo-Avilan4Nur Izzah Ismail5Ying-Hsi Lin6En Ping Yap7Song-Yi Lim8K P Myu Mai Ja9Chrishan J.A. Ramachandra10Nicole Tee11Jin Jiat Toh12Winston Shim13Philip Wong14Hector A. Cabrera-Fuentes15Derek J Hausenloy16Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, SingaporeCardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, SingaporeCardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, SingaporeCardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, SingaporeCardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, SingaporeCardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, SingaporeCardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, SingaporeCardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, SingaporeInnoheart Pte Ltd., Singapore 119844, SingaporeNational Heart Research Institute Singapore, National Heart Centre, Singapore 169609, SingaporeCardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, SingaporeNational Heart Research Institute Singapore, National Heart Centre, Singapore 169609, SingaporeInnoheart Pte Ltd., Singapore 119844, SingaporeInnoheart Pte Ltd., Singapore 119844, SingaporeNational Heart Research Institute Singapore, National Heart Centre, Singapore 169609, SingaporeCardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, SingaporeCardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore<b>Background</b>: New treatments are needed to reduce myocardial infarct size (MI) and prevent heart failure (HF) following acute myocardial infarction (AMI), which are the leading causes of death and disability worldwide. Studies in rodent AMI models showed that genetic and pharmacological inhibition of mitochondrial fission, induced by acute ischemia and reperfusion, reduced MI size. Whether targeting mitochondrial fission at the onset of reperfusion is also cardioprotective in a clinically-relevant large animal AMI model remains to be determined. <b>Methods</b>: Adult pigs (30–40 kg) were subjected to closed-chest 90-min left anterior descending artery ischemia followed by 72 h of reperfusion and were randomized to receive an intracoronary bolus of either mdivi-1 (1.2 mg/kg, a small molecule inhibitor of the mitochondrial fission protein, Drp1) or vehicle control, 10-min prior to reperfusion. The left ventricular (LV) size and function were both assessed by transthoracic echocardiography prior to AMI and after 72 h of reperfusion. MI size and the area-at-risk (AAR) were determined using dual staining with Tetrazolium and Evans blue. Heart samples were collected for histological determination of fibrosis and for electron microscopic analysis of mitochondrial morphology. <b>Results</b>: A total of 14 pigs underwent the treatment protocols (eight control and six mdivi-1). Administration of mdivi-1 immediately prior to the onset of reperfusion did not reduce MI size (MI size as % of AAR: Control 49.2 ± 8.6 vs. mdivi-1 50.5 ± 11.4; p = 0.815) or preserve LV systolic function (LV ejection fraction %: Control 67.5 ± 0.4 vs. mdivi-1 59.6 ± 0.6; p = 0.420), when compared to vehicle control. Similarly, there were no differences in mitochondrial morphology or myocardial fibrosis between mdivi-1 and vehicle control groups. <b>Conclusion</b>: Our pilot study has shown that treatment with mdivi-1 (1.2 mg/kg) at the onset of reperfusion did not reduce MI size or preserve LV function in the clinically-relevant closed-chest pig AMI model. A larger study, testing different doses of mdivi-1 or using a more specific Drp1 inhibitor are required to confirm these findings.https://www.mdpi.com/1422-0067/20/16/3972mdivi-1mitochondrial morphologycardioprotectionDrp1pigischemia/reperfusion injury |