Myocyte apoptosis during acute myocardial infarction in the mouse localizes to hypoxic regions but occurs independently of p53.

Bialik, Shani; Geenen, David L.; Sasson, Isaac; Cheng, Rendi; Horner, James W.; Evans, Sydney M.; Lord, Edith M.; Koch, Cameron J.; Kitsis, Richard N.

doi:10.1172/jci119656

Cited by 356 publications

(207 citation statements)

References 26 publications

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“…In supporting our interpretation are recent findings that myocardial apoptosis occurs during myocardial infarction and that HO-1 null mice are more prone to develop myocardial infarcts than their wild-type counterparts (Yet et al, 1999;Bialik et al, 1997).…”

Section: Psgl-1-mediated Interactions In Heart Transplantssupporting

confidence: 89%

Selectin-Mediated Interactions Regulate Cytokine Networks and Macrophage Heme Oxygenase-1 Induction in Cardiac Allograft Recipients

Coito¹,

Shaw

Li³

et al. 2002

Laboratory Investigation

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SUMMARY:Host sensitization to major histocompatibility complex (MHC) antigens is among the most critical of problems facing heart transplantation. Selectins are postulated to mediate the early adhesive events in the recruitment of leukocytes at the allograft site. We investigated the significance of selectin-P-selectin glycoprotein ligand-1 (PSGL-1)-mediated in vivo interactions in the immune cascade leading to rejection of cardiac allografts in skin presensitized rats. Infusion of a soluble recombinant form of PSGL-1 (rPSGL-Ig) during skin graft-mediated sensitization prevented Day 1.0 Ϯ 0.1 "accelerated" rejection in sensitized rat recipients, and prolonged cardiac allograft survival to Day 3.8 Ϯ 1.0 (p Ͻ 0.001). This therapy significantly depressed serum IgM levels and decreased intragraft expression of Th1 type cytokines (IL-2 and IFN-␥) as well as of IL-1␤ and MCP-1, as compared with controls, without affecting the initial number of infiltrating mononuclear cells (MNC). A profound decrease in graft-infiltrating MNC was recorded at 24 hours in rPSGL-Ig-treated rats. The expression of heme oxygenase-1 (HO-1), an inducible heat shock protein 32 that protects against oxidative cell/tissue injury, was found in approximately 14-fold higher levels in the rPSGL-Igtreated recipients as compared with controls. The HO-1 overexpression in rPSGL-Ig-treated hosts, primarily by infiltrating macrophages, was accompanied by virtual absence of myocardial infarcts and decreased frequency of TUNEL ϩ cells at the graft site. Moreover, down-regulation of HO-1 expression by zinc protoporphyrin, an HO-1 antagonist, decreased expression of antiapoptotic Bag-1 molecule in recipients conditioned with rPSGL-Ig. Thus, the blockade of selectin-PSGL-1 interactions depresses intracardiac allograft expression of Th1 type cytokines, and might inhibit the differentiation of Th1 type cells. In addition, it up-regulates HO-1 expression and protects against myocardial infarction and apoptosis. Hence, this study reports on a previously unrecognized role of selectin-PSGL-1-mediated interactions after in vivo alloantigenic challenge. (Lab Invest 2002, 82:61-70).

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Section: Psgl-1-mediated Interactions In Heart Transplantssupporting

confidence: 89%

Selectin-Mediated Interactions Regulate Cytokine Networks and Macrophage Heme Oxygenase-1 Induction in Cardiac Allograft Recipients

Coito¹,

Shaw

Li³

et al. 2002

Laboratory Investigation

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“…It is well appreciated that maintaining adequate numbers of myocytes is critical to the overall preservation of cardiac structural integrity and function after IRI 20. Given the markedly improved recovery of myocardial function in gastrin‐pretreated hearts, we next determined the effects of gastrin on I/R‐related cellular damage.…”

Section: Resultsmentioning

confidence: 99%

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

Yang

Yue

Zhang

et al. 2018

JAHA

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BackgroundIschemia/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 ResultsAdult 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.ConclusionsThese results indicate that gastrin can reduce myocardial IRI by activation of the RISK and SAFE pathways.

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“…7,18,24 Thus, we reasoned that the direct injection of the adenovirus expressing constitutively active Akt could minimize myocyte apoptosis in the affected region of the heart. Furthermore, because adenovirus-mediated gene transfer permits acute delivery of recombinant protein, we reasoned that this model would provide a more direct test of protein function than transgenic animals, in which secondary effects of chronic expression can confound analyses.…”

Section: Discussionmentioning

confidence: 99%

“…Regions of myocardial perfusion under each condition were assessed by staining with Evans blue dye (Sigma) as described previously. 18 …”

Section: Adenovirus Transduction In Vivo Transgene Detection Tunelmentioning

confidence: 99%

Akt Promotes Survival of Cardiomyocytes In Vitro and Protects Against Ischemia-Reperfusion Injury in Mouse Heart

et al. 2000

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Myocyte apoptosis during acute myocardial infarction in the mouse localizes to hypoxic regions but occurs independently of p53.

Cited by 356 publications

References 26 publications

Selectin-Mediated Interactions Regulate Cytokine Networks and Macrophage Heme Oxygenase-1 Induction in Cardiac Allograft Recipients

Selectin-Mediated Interactions Regulate Cytokine Networks and Macrophage Heme Oxygenase-1 Induction in Cardiac Allograft Recipients

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

Akt Promotes Survival of Cardiomyocytes In Vitro and Protects Against Ischemia-Reperfusion Injury in Mouse Heart

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