Chymase Inhibition Prevents Cardiac Fibrosis and Dysfunction after Myocardial Infarction in Rats

Kanemitsu, Hideo; Takai, Shinji; Tsuneyoshi, Hiroshi; Nishina, Tomohiro; Yoshikawa, Katsuhiro; Miyazaki, Mizuo; Ikeda, Tadashi; Komeda, Masashi

doi:10.1291/hypres.29.57

Cited by 64 publications

(51 citation statements)

References 35 publications

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“…On the other hand, the proteases chymase and tryptase are specific mast cell products may play unique roles in infarct healing. Chymase inhibition in a rat model of non-reperfused myocardial infarction attenuated left ventricular interstitial fibrosis and diastolic dysfunction without affecting the dilative pattern of cardiac remodeling [238] The myofibroblasts…”

Section: The Mast Cellsmentioning

confidence: 99%

The immune system and cardiac repair

Frangogiannis

2008

Pharmacological Research

568

499

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Myocardial infarction is the most common cause of cardiac injury and results in acute loss of a large number of myocardial cells. Because the heart has negligible regenerative capacity, cardiomyocyte death triggers a reparative response that ultimately results in formation of a scar and is associated with dilative remodeling of the ventricle. Cardiac injury activates innate immune mechanisms initiating an inflammatory reaction. Toll Like Receptor-mediated pathways, the complement cascade and reactive oxygen generation induce Nuclear Factor (NF)-κB activation and upregulate chemokine and cytokine synthesis in the infarcted heart. Chemokines stimulate the chemotactic recruitment of inflammatory leukocytes into the infarct, while cytokines promote adhesive interactions between leukocytes and endothelial cells, resulting in transmigration of inflammatory cells into the site of injury. Monocyte subsets play distinct roles in phagocytosis of dead cardiomyocytes and in granulation tissue formation through the release of growth factors. Clearance of dead cells and matrix debris may be essential for resolution of inflammation and transition into the reparative phase. Transforming Growth Factor (TGF)-β plays a crucial role in cardiac repair by suppressing inflammation while promoting myofibroblast phenotypic modulation and extracellular matrix deposition. Myofibroblast proliferation and angiogenesis result in formation of highly vascularized granulation tissue. As the healing infarct matures, fibroblasts become apoptotic and a collagen-based matrix is formed, while many infarct neovessels acquire a muscular coat and uncoated vessels regress. Timely resolution of the inflammatory infiltrate and spatial containment of the inflammatory and reparative response into the infarcted area are essential for optimal infarct healing. Targeting inflammatory pathways following infarction may reduce cardiomyocyte injury and attenuate adverse remodeling. In addition, understanding the role of the immune system in cardiac repair is necessary in order to design optimal strategies for cardiac regeneration.

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Section: The Mast Cellsmentioning

confidence: 99%

The immune system and cardiac repair

Frangogiannis

2008

Pharmacological Research

568

499

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“…TGF-β is a major stimulator of myocardial fibrosis and is closely involved in the promotion of cardiac fibrosis. To clarify the role of chymase-dependent TGF-β activation, we evaluated whether chymase inhibition prevents cardiac fibrosis and cardiac dysfunction after myocardial infarction in rats that have no angiotensin IIforming chymase in their hearts (17). Chymase activity was significantly increased after myocardial infarction, but it was significantly reduced by chymase inhibitor treatment (17).…”

Section: Effects Of Chymase Inhibitor In Ischemic Heart Diseasesmentioning

confidence: 99%

“…To clarify the role of chymase-dependent TGF-β activation, we evaluated whether chymase inhibition prevents cardiac fibrosis and cardiac dysfunction after myocardial infarction in rats that have no angiotensin IIforming chymase in their hearts (17). Chymase activity was significantly increased after myocardial infarction, but it was significantly reduced by chymase inhibitor treatment (17). Both the fibrotic area and the mRNA levels of collagen I and collagen III were also significantly decreased by the chymase inhibitor treatment.…”

Section: Effects Of Chymase Inhibitor In Ischemic Heart Diseasesmentioning

confidence: 99%

Multiple Mechanisms for the Action of Chymase Inhibitors

Jin

Miyazaki

2012

J Pharmacol Sci

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Abstract. Angiotensin II plays an important role in regulating blood pressure. Moreover, angiotensin II directly promotes organ damage by inducing expression of various genes, such as transforming growth factor (TGF)-β and matrix metalloproteinase (MMP)-9 precursors. Blockade of angiotensin II has been shown to not only lower blood pressure, but also to prevent cardiovascular and renal dysfunction and fibrosis. Inhibition of TGF-β and MMP-9 has also been shown to prevent cardiovascular and renal damage. A mast cell-produced enzyme, chymase, generates angiotensin II and also converts precursors of TGF-β and MMP-9 to their active forms. Chymase also strongly promotes accumulation of inflammatory cells. These multiple functions of chymase may play an important role in the development and promotion of various diseases. In fact, chymase inhibitors have been shown to prevent nonalcoholic steatohepatitis, intestinal inflammation, and adhesion formation after surgery and cardiovascular and renal damage. On the other hand, chymase inhibitors, unlike angiotensin-converting enzyme inhibitors and angiotensin II blockers, have no blood pressure-lowering effect despite blocking angiotensin II formation. Thus, chymase inhibitors may be useful for preventing damage to various organs via multiple mechanisms without lowering blood pressure.

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“…In rodents, chymase inhibitor monotherapy improved survival and reduced post-MI cardiac hypertrophy and dysfunction (5,6). Although these studies, and clinical trials, together suggest an Ang II-independent mechanism of action of chymase inhibitors, other studies with chymase inhibitor monotherapy were negative (7,8).…”

mentioning

confidence: 99%

IGF-1 degradation by mouse mast cell protease 4 promotes cell death and adverse cardiac remodeling days after a myocardial infarction

Tejada

Tan

Torres

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Heart disease is a leading cause of death in adults. Here, we show that a few days after coronary artery ligation and reperfusion, the ischemia-injured heart elaborates the cardioprotective polypeptide, insulin-like growth factor-1 (IGF-1), which activates IGF-1 receptor prosurvival signaling and improves cardiac left ventricular systolic function. However, this signaling is antagonized by the chymase, mouse mast cell protease 4 (MMCP-4), which degrades IGF-1. We found that deletion of the gene encoding MMCP-4 (Mcpt4), markedly reduced late, but not early, infarct size by suppressing IGF-1 degradation and, consequently, diminished cardiac dysfunction and adverse structural remodeling. Our findings represent the first demonstration to our knowledge of tissue IGF-1 regulation through proteolytic degradation and suggest that chymase inhibition may be a viable therapeutic approach to enhance late cardioprotection in postischemic heart disease.insulin-like growth factor-1 | chymase | mouse mast cell protease 4 | ischemia-reperfusion injury | cardioprotection

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Chymase Inhibition Prevents Cardiac Fibrosis and Dysfunction after Myocardial Infarction in Rats

Cited by 64 publications

References 35 publications

The immune system and cardiac repair

The immune system and cardiac repair

Multiple Mechanisms for the Action of Chymase Inhibitors

IGF-1 degradation by mouse mast cell protease 4 promotes cell death and adverse cardiac remodeling days after a myocardial infarction

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