Mast Cells Cause Apoptosis of Cardiomyocytes and Proliferation of Other Intramyocardial Cells In Vitro

Hara, Masatake; Matsumori, Akira; Ono, Koh; Kido, Hiroshi; Hwang, Myung-Woo; Miyamoto, Tadashi; Iwasaki, Atsushi; Okada, Masaharu; Nakatani, Kazuki; Sasayama, Shígetake

doi:10.1161/01.cir.100.13.1443

Cited by 107 publications

(79 citation statements)

References 27 publications

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“…21,22 Mast cell chymase induces the proliferation of cardiac fibroblasts and apoptosis of cardiac myocytes. 16 We have previously reported that IL-1 , a prominent cytokine in cardiac remodeling, is upregulated in the chronic stage of EMC viral myocarditis, 27 and it has also been implicated in fibrosis after myocardial infarction. 28 The human mast cell chymase, the counterpart of mMCP-5, which was upregulated in the present study, converts the precursor IL-1 to an active form, 15 suggesting that mMCPs play a role in cardiac remodeling.…”

Section: Discussionmentioning

confidence: 97%

Gene Expression of Cardiac Mast Cell Chymase and Tryptase in a Murine Model of Heart Failure Caused by Viral Myocarditis

Kitaura-Inenaga

Hara

Higuchi

et al. 2003

Circ J

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Section: Discussionmentioning

confidence: 97%

Gene Expression of Cardiac Mast Cell Chymase and Tryptase in a Murine Model of Heart Failure Caused by Viral Myocarditis

Kitaura-Inenaga

Hara

Higuchi

et al. 2003

Circ J

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“…39 Protease-induced apoptosis is not a specific phenomena for chymase and SMCs, inasmuch as elastase and proteinase 3 (neutrophil serine proteases) can induce the apoptosis of endothelial cells, 40 ␣-chymotrypsin and trypsin can induce the apoptosis of neutrophils, 41 and chymase can induce the apoptosis of cardiomyocytes. 42 However, the observation that granule-bound natural chymase can induce apoptosis, even in the presence of natural inhibitors, might support a role for mast cell-derived granule-bound chymase compared with other neutral proteases at the site of atherogenesis in inducing apoptosis in vivo. Interestingly, peripheral blood monocytes, lymphocytes, several human leukemic cell lines (THP-1, HL-60, and K562), murine L929 fibroblasts, mouse perito- neal macrophages, 41 and myocardial fibroblasts 42 failed to undergo apoptosis after treatment with proteases, suggesting that cells also differ in their susceptibility to undergo protease-induced apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…42 However, the observation that granule-bound natural chymase can induce apoptosis, even in the presence of natural inhibitors, might support a role for mast cell-derived granule-bound chymase compared with other neutral proteases at the site of atherogenesis in inducing apoptosis in vivo. Interestingly, peripheral blood monocytes, lymphocytes, several human leukemic cell lines (THP-1, HL-60, and K562), murine L929 fibroblasts, mouse perito- neal macrophages, 41 and myocardial fibroblasts 42 failed to undergo apoptosis after treatment with proteases, suggesting that cells also differ in their susceptibility to undergo protease-induced apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Mast cell chymase induces apoptosis of vascular smooth muscle cells

et al. 2000

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Abstract-In human coronary atheromas, the numbers of degranulated mast cells and of apoptotic smooth muscle cells (SMCs) are increased. Accordingly, the possibility exists that mast cells participate in the regulation of SMC apoptosis in the lesions. Mast cells isolated from the serosal cavities of rats were stimulated to release their secretory granules. The neutral protease chymase, present in the exocytosed granules, was found to induce apoptosis when added to rat aortic SMCs in culture. The chymase-induced apoptosis of SMCs was detected by flow cytometry, microscopic analysis of cellular morphology, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL), and electrophoretic demonstration of DNA laddering. Chymase induced SMC apoptosis in a dose-and time-dependent manner, and its proteolytic activity was essential for the proapoptotic effect. In addition to rat chymase, recombinant human chymase was also found to induce apoptosis of human coronary artery SMCs in culture. Key Words: apoptosis Ⅲ smooth muscle Ⅲ atherosclerosis Ⅲ mast cells Ⅲ chymase S mooth muscle cells (SMCs) are the main cellular component in atherosclerotic lesions, and their number and activity largely determine the thickness of the intima. 1 During the final stages of atherosclerosis, the clinical relevance of the thickness of the intima is apparent: a thick intima (fibrous cap) overlying a lipid-rich core of an atheroma protects it from rupturing, whereas a thin cap predisposes it to rupture. 2 The concept has been put forward that the fibrous cap of an atheroma is a dynamic structure in which connective tissue matrix is produced and maintained by SMCs. 3 Accordingly, reduced production of the extracellular matrix due to decreased SMC number, either by necrotic or apoptotic cell death, would weaken the cap and potentiate the risk of cap rupture.Recent findings have demonstrated that SMCs of human coronary and carotid atheromas undergo apoptosis. 4 -7 Interestingly, it has been shown that SMCs isolated from human coronary atherosclerotic plaques are more prone to apoptosis than are SMCs from normal vessels. 8 The SMCs undergoing apoptosis are localized mainly in the fibrous caps of the atheromas and are accompanied by the presence of inflammatory cells. 6,9 In the inflammatory infiltrates, mast cells are also present. 10 -12 Our previous investigations have used isolated rat serosal mast cells, which, like human mast cells, release on stimulation an array of vasoactive mediators, proteoglycans, and neutral proteases. 13,14 The rat mast cells have been shown to be a useful model for studying various molecular aspects relevant to human atherogenesis. 15 Chymase is contained in the cytoplasmic granules of rat serosal mast cells and, on their degranulation, is secreted within expelled granules. 14 In the extracellular fluid, the soluble components of the exocytosed granules (ie, histamine, chondroitin sulfate proteoglycans, and a fraction of heparin sulfate proteoglycans) are solubilized and released from the granules. ...

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“…IGF-1 mRNA levels were unchanged initially, but increased markedly between 48 and 72 h after I/R in WT hearts (Table S4). In 72-h post-I/R hearts, IGF-1 mRNA was enriched in cardiomyocytes (relative expression: 1 ± 0.22 versus 0.27 ± 0.027 18 S-normalized IGF-1 mRNA transcripts in cardiomyocytes and noncardiomyocytes, respectively, n = 3, P < 0.05), suggesting that these cells are the main source of IGF-1 production. In contrast to IGF-1 mRNA levels, cardiac IGF-1 protein levels fell by 35% between 48 and 72 h after I/R (P < 0.001) (Fig.…”

Section: Beneficial Effects Of Mcpt4 Deletion In Postischemic Hearts Arementioning

confidence: 94%

“…2 A-C) and could be due to late preservation of myocardium after I/R through a suppression of deleterious effects of MMCP-4 on cardiomyocyte survival. We considered this possibility because prior in vitro work has shown that mast cell serine proteinases cause cultured rat neonatal cardiomyocyte to undergo apoptosis (18); albeit that the apoptosis mechanism was not explored.…”

Section: Beneficial Effects Of Mcpt4 Deletion In Postischemic Hearts Arementioning

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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Mast Cells Cause Apoptosis of Cardiomyocytes and Proliferation of Other Intramyocardial Cells In Vitro

Cited by 107 publications

References 27 publications

Gene Expression of Cardiac Mast Cell Chymase and Tryptase in a Murine Model of Heart Failure Caused by Viral Myocarditis

Gene Expression of Cardiac Mast Cell Chymase and Tryptase in a Murine Model of Heart Failure Caused by Viral Myocarditis

Mast cell chymase induces apoptosis of vascular smooth muscle cells

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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