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Cardiomyocyte-specific transforming growth factor ? suppression blocks neutrophil infiltration, augments multiple cytoprotective cascades, and reduces early mortality after myocardial infarction.

ABSTRACT: Wound healing after myocardial infarction involves a highly regulated inflammatory response that is initiated by the appearance of neutrophils to clear out dead cells and matrix debris. Neutrophil infiltration is controlled by multiple secreted factors, including the master regulator transforming growth factor ? (TGF?). Broad inhibition of TGF? early postinfarction has worsened post-myocardial infarction remodeling; however, this signaling displays potent cell specificity, and targeted suppression particularly in the myocyte could be beneficial.Our aims were to test the hypothesis that targeted suppression of myocyte TGF? signaling ameliorates postinfarct remodeling and inflammatory modulation and to identify mechanisms by which this may be achieved.Mice with TGF? receptor-coupled signaling genetically suppressed only in cardiac myocytes (conditional TGF? receptor 1 or 2 knockout) displayed marked declines in neutrophil recruitment and accompanying metalloproteinase 9 activation after infarction and were protected against early-onset mortality due to wall rupture. This is a cell-specific effect, because broader inhibition of TGF? signaling led to 100% early mortality due to rupture. Rather than by altering fibrosis or reducing the generation of proinflammatory cytokines/chemokines, myocyte-selective TGF? inhibition augmented the synthesis of a constellation of highly protective cardiokines. These included thrombospondin 4 with associated endoplasmic reticulum stress responses, interleukin-33, follistatin-like 1, and growth and differentiation factor 15, which is an inhibitor of neutrophil integrin activation and tissue migration.These data reveal a novel role of myocyte TGF? signaling as a potent regulator of protective cardiokine and neutrophil-mediated infarct remodeling.

SUBMITTER: Rainer PP

PROVIDER: S-EPMC3997999 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Cardiomyocyte-specific transforming growth factor β suppression blocks neutrophil infiltration, augments multiple cytoprotective cascades, and reduces early mortality after myocardial infarction.

Rainer Peter P PP Hao Scarlett S Vanhoutte Davy D Lee Dong Ik DI Koitabashi Norimichi N Molkentin Jeffery D JD Kass David A DA

Circulation research 20140226 8

<h4>Rationale</h4>Wound healing after myocardial infarction involves a highly regulated inflammatory response that is initiated by the appearance of neutrophils to clear out dead cells and matrix debris. Neutrophil infiltration is controlled by multiple secreted factors, including the master regulator transforming growth factor β (TGFβ). Broad inhibition of TGFβ early postinfarction has worsened post-myocardial infarction remodeling; however, this signaling displays potent cell specificity, and ...[more]

PMID: 24573206

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Project description:Myocardial infarction (MI) is one of the most common cardiac emergencies with high morbidity and is a leading cause of death worldwide. Since MI could develop into a life-threatening emergency and could also seriously affect the life quality of patients, continuous efforts have been made to create an effective strategy to prevent the occurrence of MI and reduce MI-related mortality. Numerous studies have confirmed that neutrophils play important roles in inflammation and innate immunity, which provide the first line of defense against microorganisms by producing inflammatory cytokines and chemokines, releasing reactive oxygen species, and degranulating components of neutrophil cytoplasmic granules to kill pathogens. Recently, researchers reported that neutrophils are closely related to the severity and prognosis of patients with MI, and neutrophil to lymphocyte ratio in post-MI patients had predictive value for major adverse cardiac events. Neutrophils have been increasingly recognized to exert important functions in MI. Especially, granule proteins released by neutrophil degranulation after neutrophil activation have been suggested to involve in the process of MI. This article reviewed the current research progress of neutrophil granules in MI and discusses neutrophil degranulation associated diagnosis and treatment strategies. Video abstract Neutrophils played a crucial role throughout the process of MI, and neutrophil degranulation was the crucial step for the regulative function of neutrophils. Both neutrophils infiltrating and neutrophil degranulation take part in the injury and repair process immediately after the onset of MI. Since different granule subsets (e g. MPO, NE, NGAL, MMP-8, MMP-9, cathelicidin, arginase and azurocidin) released from neutrophil degranulation show different effects through diverse mechanisms in MI. In this review, we reviewed the current research progress of neutrophil granules in MI and discusses neutrophil degranulation associated diagnosis and treatment strategies. Myeloperoxidase (MPO); Neutrophil elastase (NE); Neutrophil gelatinase-associated lipocalin (NGAL); Matrix metalloproteinase 8 (MMP-8); Matrix metalloproteinase 9 (MMP-9).

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Cardiomyocyte-specific transforming growth factor ? suppression blocks neutrophil infiltration, augments multiple cytoprotective cascades, and reduces early mortality after myocardial infarction.

Publications

Cardiomyocyte-specific transforming growth factor β suppression blocks neutrophil infiltration, augments multiple cytoprotective cascades, and reduces early mortality after myocardial infarction.

Similar Datasets

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