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

Kitaura-Inenaga, Katsura; Hara, Masatake; Higuchi, Kazuhiro; Yamamoto, Keita; Yamaki, Akira; Ono, Koh; Nakano, Atsushi; Kinoshita, Makoto; Sasayama, Shígetake; Matsumori, Akira

doi:10.1253/circj.67.881

Cited by 41 publications

(34 citation statements)

References 33 publications

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“…Finally, a marked increase in cardiac mMCP-4 and mMCP-5 mRNA levels has been shown in a mouse model of heart failure (Kitaura-Inenaga et al, 2003), thus confirming the present results as far as the presence of both chymase isoforms are concerned in cardiac homogenates.…”

Section: Discussionsupporting

confidence: 91%

Chymase-Dependent Conversion of Big Endothelin-1 in the Mouse in Vivo

Simard

Jin²,

Miyazaki³

et al. 2008

J Pharmacol Exp Ther

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The aim of this study was to identify the role of chymase in the conversion of exogenously administered Big endothelin-1 in the mouse in vivo. Real-time polymerase chain reaction analysis detected mRNA of mucosal mast cell chymases 4 and 5, endothelin-converting enzyme 1a, and neutral endopeptidase 24.11 in pulmonary, cardiac, and aorta homogenates derived from C57BL/6J mice, with the latter tissue expressing the highest levels of both chymase isoforms. Furthermore, hydrolysis of a fluorogenic peptide substrate, Suc-Leu-Leu-Val-Tyr-7-amino-4-methylcoumarin, was sensitive to the chymase inhibitors Suc-ValPro-PheS)-Gly-X-Phe-al, where X can be the amino acid Leu, Val, or Ile) (100 M) in supernatants extracted from the same tissue homogenates. In anesthetized mice, Big endothelin-1, endothelin-1 (1-31), and endothelin-1 triggered pressor responses (ED 50 s, 0.67, 0.89, and 0.16 nmol/kg) that were all reduced or potentiated by selective endothelin ET A or ET B receptor antagonists,, each at 1 mg/kg. The pressor responses to big endothelin-1 were significantly reduced by the neutral endopeptidase inhibitor thiorphan (DL-3-mercapto-2-benzylpropanoylglycine) (1 mg/kg) or the endothelin-converting enzyme inhibitorIn contrast, the responses to endothelin-1 (1-31) were abolished by thiorphan but unaffected by CGS 35066. In addition, Suc-Val-Pro-Phe P (OPh) 2 (20 -40 mg/kg) reduced, by more than 60%, the hemodynamic response to big endothelin-1 but not to endothelin-1 (1-31) and endothelin-1. Finally, intravenous administration of big endothelin-1 induced Suc-Val-Pro-Phe P -(OPh) 2 -sensitive increases in plasma-immunoreactive levels of endothelin-1 (1-31) and endothelin-1. The present study suggests that chymase plays a pivotal role in the conversion and cardiovascular properties of big endothelin-1 in vivo. , 2003). It is noteworthy that tissues derived from mice knockdown for both ECE-1 and ECE-2, which are nonviable past late gestational stages, still contain two thirds of mature endothelin peptides found in wild-type congeners, thus suggesting an important role for other pro- The authors of the present manuscript declare that there are no financial links, including consultancies with manufacturers of material or devices described in the article, and no links to the pharmaceutical industry or regulatory agencies or any other potential conflicts of interest.Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.108.142992. -788, N-[N-[N-[(2,6-dimethyl-1-piperidinyl) ABBREVIATIONS: ECE, endothelin-converting enzyme; ET, endothelin; phosphoramidon, N-(␣-rhamno-pyranosyl-oxy-hydroxy-phosphinyl)-Leu-

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Section: Discussionsupporting

confidence: 91%

Chymase-Dependent Conversion of Big Endothelin-1 in the Mouse in Vivo

Simard

Jin²,

Miyazaki³

et al. 2008

J Pharmacol Exp Ther

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“…We confirmed that the number of mast cells was increased on day 14 after EMCV inoculation, when myocardial fibrosis becomes apparent, 26 and that the protein level of SCF in the heart had already increased on day 7 in the EMCV myocarditis (H.H., MD, T.M., and A.M., unpublished data, 2002). Using our EMCV myocarditis model in these W/W V and Sl/Sl d strains of mice, we observed that mast cell deficiency had beneficial effects in this disorder.…”

Section: Discussionsupporting

confidence: 69%

“…29 We have reported that the gene expression of mast cell chymase and tryptase was upregulated in the acute phase of viral myocarditis and rose further in the subacute phase of CHF. 26 This activation coincided with the development of myocardial necrosis and fibrosis and correlated with the upregulation of MMP-9 and type-I procollagen, suggesting that mast cell chymase and tryptase participate in the acute inflammatory reaction as well as the remodeling process associated with acute viral myocarditis.…”

Section: Discussionmentioning

confidence: 86%

Mast Cells Play a Critical Role in the Pathogenesis of Viral Myocarditis

et al. 2008

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“…19) Role of mast cell proteases in fibrosis has been documented in several other studies. [20][21][22] A significant correlation is obtained between myocardial fibrosis and cardiac mast cell density in the present study.…”

Section: )supporting

confidence: 72%

“…20) Involvement of mast cells in viral myocarditis induced heart failure has been described previously. 22) However, this study may be the first report to elucidate and confirm such notion with the use of mast cell stabilizer and co-localization of mast cells in the fibrotic region in a model of postmyocarditis DCM. Myocardial fibrosis has been widely implicated for the diastolic dysfunction in DCM.…”

Section: )mentioning

confidence: 56%