Gastrin Protects Against Myocardial Ischemia/Reperfusion Injury via Activation of RISK (Reperfusion Injury Salvage Kinase) and SAFE (Survivor Activating Factor Enhancement) Pathways

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Abstract

Background

Ischemia/reperfusion injury (IRI) is one of the most predominant complications of ischemic heart disease. Gastrin has emerged as a regulator of cardiovascular function, playing a key protective role in hypoxia. Serum gastrin levels are increased in patients with myocardial infarction, but the pathophysiogical significance of this finding is unknown. The purpose of this study was to determine whether and how gastrin protects cardiac myocytes from IRI.

Methods and Results

Adult male Sprague‐Dawley rats were used in the experiments. The hearts in living rats or isolated Langendorff‐perfused rat hearts were subjected to ischemia followed by reperfusion to induce myocardial IRI. Gastrin, alone or with an antagonist, was administered before the induction of myocardial IRI. We found that gastrin improved myocardial function and reduced the expression of myocardial injury markers, infarct size, and cardiomyocyte apoptosis induced by IRI. Gastrin increased the phosphorylation levels of ERK1/2 (extracellular signal‐regulated kinase 1/2), AKT (protein kinase B), and STAT3 (signal transducer and activator of transcription 3), indicating its ability to activate the RISK (reperfusion injury salvage kinase) and SAFE (survivor activating factor enhancement) pathways. The presence of inhibitors of ERK1/2, AKT, or STAT3 abrogated the gastrin‐mediated protection. The protective effect of gastrin was via CCK2R (cholecystokinin 2 receptor) because the CCK2R blocker CI988 prevented the gastrin‐mediated protection of the heart with IRI. Moreover, we found a negative correlation between serum levels of cardiac troponin I and gastrin in patients with unstable angina pectoris undergoing percutaneous coronary intervention, suggesting a protective effect of gastrin in human cardiomyocytes.

Conclusions

These results indicate that gastrin can reduce myocardial IRI by activation of the RISK and SAFE pathways.

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Most cited references 46

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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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Signalling via the reperfusion injury signalling kinase (RISK) pathway links closure of the mitochondrial permeability transition pore to cardioprotection.

Michael Duchen, D Yellon, Derek Hausenloy … (2006)

Post-ischemic interventions that activate phosphatidylinositol-3-OH kinase (PI3K)-Akt or ERK1/2 pro-survival kinases (the so-called "reperfusion injury signalling kinase (RISK) pathway") during the first few minutes of reperfusion protect against lethal reperfusion-induced injury. We have previously shown that insulin protects against reperfusion-induced injury via activation of the PI3K-Akt pathway. In addition, opening of the mitochondrial permeability transition pore (mPTP) at the time of reperfusion is a major determinant of lethal reperfusion-induced injury, and pharmacologically inhibiting it is cardioprotective. In this study, we examined the relationship between the pro-survival kinase pathways and mPTP opening. Specifically, we tested the hypothesis that activation of the pro-survival kinase pathway by insulin protects cardiomyocytes by reducing the probability of mPTP opening upon reperfusion. Laser illumination of the fluorophore, tetramethyl rhodamine methyl ester (TMRM), was used to induce oxidative stress in the preparation of adult rat ventricular cardiomyocytes. Maintained illumination ultimately induces mPTP opening, detected as a global mitochondrial depolarization, followed by ATP depletion and rigor contracture. Insulin significantly delayed mPTP opening by a factor of approximately 1.7-fold (P<0.001). The effect of insulin was prevented by Wortmannin and by LY-294002, inhibitors of the PI3K pathway, by SH-6, a selective inhibitor of Akt, and by L-NAME, an inhibitor of nitric oxide production. The expression of a dominant negative construct of Akt eliminated the effect of insulin in delaying mPTP opening in a cardiac cell line. Furthermore, the overexpression of constitutively active Akt was sufficient to maximally delay mPTP opening. These results indicate that activation of the PI3K-Akt pro-survival kinase pathway inhibits opening of the mPTP, and demonstrate an important link between the survival kinases and the mPTP.

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Phosphorylation of GSK-3β mediates intralipid-induced cardioprotection against ischemia/reperfusion injury.

Mansoureh Eghbali, Pattanathu Rahman, Jingyuan Li … (2011)

Intralipid (Sigma, St. Louis, MO), a brand name for the first safe fat emulsion for human use, has been shown to be cardioprotective. However, the mechanism of this protection is not known. The authors investigated the molecular mechanism(s) of Intralipid-induced cardioprotection against ischemia/reperfusion injury, particularly the role of glycogen synthase kinase-3β (GSK-3β) and mitochondrial permeability transition pore in this protective action. In vivo rat hearts or isolated Langendorff-perfused mouse hearts were subjected to ischemia followed by reperfusion with Intralipid (1% in ex vivo and one bolus of 20% in in vivo) or vehicle. The hemodynamic function, infarct size, threshold for the opening of mitochondrial permeability transition pore, and phosphorylation levels of protein kinase B (Akt)/extracellular signal regulating kinase (ERK)/GSK-3β were measured. Administration of Intralipid at the onset of reperfusion resulted in approximately 70% reduction in infarct size in the in vivo rat model. Intralipid also significantly improved functional recovery of isolated Langendorff-perfused mouse hearts as the rate pressure product was increased from 2,999 ± 863 mmHg*beats/min in the control group to 13,676 ± 611 mmHg*beats/min (mean±SEM) and the infarct size was markedly smaller (18.3 ± 2.4% vs. 54.8 ± 2.9% in the control group, P < 0.01). The Intralipid-induced cardioprotection was fully abolished by LY294002, a specific inhibitor of PI3K, but only partially by PD98059, a specific ERK inhibitor. Intralipid also increased the phosphorylation levels of Akt/ERK1/glycogen synthase kinase-3β by eightfold, threefold, and ninefold, respectively. The opening of mitochondrial permeability transition pore was inhibited by Intralipid because calcium retention capacity was higher in the Intralipid group (274.3 ± 8.4 nM/mg vs. 168.6 ± 9.6 nM/mg in the control group). Postischemic treatment with Intralipid inhibits the opening of mitochondiral permeability transition pore and protects the heart through glycogen synthase kinase-3β via PI3K/Akt/ERK pathways.

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Author and article information

Contributors

Hongyong Wang: whysir@aliyun.com

Chunyu Zeng: chunyuzeng01@163.com

Journal

Journal ID (nlm-ta): J Am Heart Assoc

Journal ID (iso-abbrev): J Am Heart Assoc

Journal ID (doi): 10.1002/(ISSN)2047-9980

Journal ID (publisher-id): JAH3

Journal ID (hwp): ahaoa

Title: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease

Publisher: John Wiley and Sons Inc. (Hoboken )

ISSN (Electronic): 2047-9980

Publication date (Electronic): 12 July 2018

Publication date Collection: 17 July 2018

Volume: 7

Issue: 14 ( doiID: 10.1002/jah3.2018.7.issue-14 )

Electronic Location Identifier: e005171

Affiliations

[ ¹ ] Department of Cardiology Chongqing Institute of Cardiology Daping Hospital Third Military Medical University Chongqing China

[ ² ] Department of Cardiology North Sichuan Medical College First Affiliated Hospital Nanchong Sichuan China

[ ³ ] Cardiovascular Research Center & Department of Physiology Temple University School of Medicine Philadelphia PA

[ ⁴ ] Department of Statistics The George Washington University Washington DC

[ ⁵ ] Division of Renal Disease & Hypertension The George Washington University School of Medicine & Health Sciences Washington DC

Author notes

[*] [* ] Correspondence to: Chunyu Zeng, MD, PhD, and Hongyong Wang, MD, PhD, Department of Cardiology, Chongqing Institute of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China. E‐mails: chunyuzeng01@ 123456163.com ; whysir@ 123456aliyun.com

[†]

Dr Yang and Dr Yue contributed equally to this work.

Article

Publisher ID: JAH33311

DOI: 10.1161/JAHA.116.005171

PMC ID: 6064830

PubMed ID: 30005556

SO-VID: e614d9e7-740a-4030-b26d-c831a57b60b9

License:

This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

History

Date received : 29 November 2016

Date accepted : 16 May 2018

Page count

Figures: 9, Tables: 1, Pages: 14, Words: 7440

Funding

Funded by: National Natural Science Foundation of China

Award ID: 31430043

Award ID: 31730043

Funded by: Program of Innovative Research Team by National Natural Science Foundation

Award ID: 81721001

Funded by: National Institutes of Health

Award ID: R37HL023081‐37

Award ID: R01DK039308‐30

Award ID: P01HL074940‐12

Custom metadata

source-schema-version-number 2.0

component-id jah33311

cover-date 17 July 2018

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.3 mode:remove_FC converted:20.07.2018

ScienceOpen disciplines: Cardiovascular Medicine

Keywords: gastrin,ischemia/reperfusion injury,langendorff,reperfusion injury salvage kinase,risk (reperfusion injury salvage kinase),safe (survivor activating factor enhancement),myocardial infarction,ischemia,mechanisms

Data availability:

ScienceOpen disciplines: Cardiovascular Medicine

Keywords: gastrin, ischemia/reperfusion injury, langendorff, reperfusion injury salvage kinase, risk (reperfusion injury salvage kinase), safe (survivor activating factor enhancement), myocardial infarction, ischemia, mechanisms

Gastrin Protects Against Myocardial Ischemia/Reperfusion Injury via Activation of RISK (Reperfusion Injury Salvage Kinase) and SAFE (Survivor Activating Factor Enhancement) Pathways

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Abstract

Background

Methods and Results

Conclusions

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Karger: Cardiovascular System

Most cited references 46

Ischemia/Reperfusion.

Signalling via the reperfusion injury signalling kinase (RISK) pathway links closure of the mitochondrial permeability transition pore to cardioprotection.

Phosphorylation of GSK-3β mediates intralipid-induced cardioprotection against ischemia/reperfusion injury.

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