Disease relevance of Mcpt1

• Spontaneously hypertensive rats show elevated chymase expression and increased chymostatin-inhibitable angiotensin-converting activity, suggesting a possible role for this novel enzyme in the pathophysiology of hypertension [1].
• Chymase inhibition prevents cardiac fibrosis and dysfunction after myocardial infarction in rats [2].
• One day after the ligation, rats were randomized into 2 groups: 1) a chymase-treated group that received 10 mg/kg per day of the chymase inhibitor NK3201 orally for 4 weeks; and 2) a vehicle group of non-treated rats with myocardial infarction [2].
• Our results show that the systemic secretion of RMCP II coincides with the immune expulsion of these nematodes, demonstrating clearly for the first time that rat MMC are functionally active during the immune elimination of primary nematode infections [3].
• Release of the mucosal mast cell granule chymase, rat mast cell protease-II, during anaphylaxis is associated with the rapid development of paracellular permeability to macromolecules in rat jejunum [4].

High impact information on Mcpt1

• Angiotensin II-forming activity in a reconstructed ancestral chymase [5].
• Two of the major rat mast cell proteases, rat mast cell protease 1 (RMCP-1) and RMCP-2, have for many years served as important phenotypic markers for studies of various aspects of mast cell (MC) biology [6].
• To examine the effects of RMCP-II more directly 1 mg of the highly purified chymase was introduced into the cranial mesenteric artery in ex vivo perfused normal rats [4].
• We assayed the activity of the endogenous enzyme and of a recombinant, epitope-tagged chymase in transfected smooth muscle cells and showed that Ang II production from Ang I can be inhibited with chymostatin, but not EDTA or captopril [1].
• The cDNA encompasses 953 nucleotides, encodes 247 amino acids, and exhibits 74% and 80% homology in amino acid sequence to rat mast cell chymase I and II, respectively [1].

Biological context of Mcpt1

• A disulfide bond near the active site seryl residue and substrate binding site, present in pancreatic and plasma serine proteases, is not found in RMCP I or in the other cellular proteases [7].
• The results also suggest that chymase may play a role in heart remodeling by increasing Ang II formation and activating MMP-9, and the regulation of collagen I gene expression [8].
• RESULTS: A model of transgenic mice with selective overexpression of a rat myosin light chain 2 promoter-human heart chymase (MLC(2-)-hChymase) fusion gene was produced [8].
• Additionally, the hydrolysis of angiotensin I catalyzed by chymotrypsin, but not by RMCP I, resulted in the generation of angiotensin II as an intermediate product [9].
• The substrate specificity of rat mast cell protease I (RMCP I), a chymotrypsin-like serine protease localized in the secretory granules of mast cells, was compared to that of bovine alpha-chymotrypsin by using several peptide and protein substrates of known amino acid sequences [9].

Anatomical context of Mcpt1

• We now describe the cloning of a full-length cDNA encoding a novel chymase from rat vascular smooth muscle cells [1].
• This chymase was induced in hypertrophied rat pulmonary arteries, with 11-fold and 8-fold higher chymase mRNA levels in aortic and pulmonary artery smooth muscle cells from spontaneously hypertensive than in corresponding tissues from normotensive rats [1].
• Angiotensin II-forming chymase is expressed in the pulmonary arteries of the monocrotaline-induced pulmonary hypertensive rats, but its actual role is unclear [10].
• Based on the sequence of RMCP1 or RMCP2 cDNAs, selective oligoprobes were designed and their specificity established by Northern blot analysis of mRNAs purified from tongue and jejunum, two tissues containing selectively type 1 and 2 protease, respectively [11].
• Chymase activity in the non-infarcted myocardium was significantly increased in the vehicle group, but it was significantly reduced by chymase inhibitor treatment [2].

Associations of Mcpt1 with chemical compounds

• While greater than 80% of angiotensin II (Ang II) formation in the human heart and greater than 60% in arteries appears to result from chymase activity, no cardiovascular cell-expressed chymase has been previously reported [1].
• CONCLUSIONS: We have demonstrated selective overexpression of human chymase gene in the heart of transgenic mice, and the results support the hypothesis of a dual Ang II-forming pathway from chymase and ACE in the cardiac tissue in vivo [8].
• In this study we found that remnant chymase, by proteolyzing human serum and human aortic intimal fluid, prevents these two physiologic fluids from effectively inducing cholesterol efflux from cultured macrophage foam cells [12].
• RESULTS: Intracisternal injection of the TRH analogue RX 77368 (30 ng) induced a transient increase in intestinal release of RMCP II and PGD2 that was abolished by dox-antrazole [13].
• However, both systemic capsaicin and indo-methacin enhanced RMCP II release [13].

Enzymatic interactions of Mcpt1

• The results are consistent with a model according to which the proteolytic degradation of LDL by mast cell granules results from coordinated action of the two granule-bound enzymes, whereby the chymase first cleaves peptides from the apolipoprotein B of LDL, and thereafter the carboxypeptidase A cleaves amino acids from the peptides formed [14].

Regulatory relationships of Mcpt1

• In the present investigation it was shown that RMCP-1 is inhibited by vitronectin (VN), an RGD-containing adhesive glycoprotein with heparin-binding properties [15].

Other interactions of Mcpt1

• A computer search for homology indicates 73% and 33% sequence identity of RMCP I with rat mast cell protease II from mucosal mast cells and bovine chymotrypsin A, respectively [7].
• RESULTS: Acute stress increased skin vascular permeability and CRH content, while it decreased RMCP-1 [16].
• However, recent evidence indicates the existence of an alternative chymase-mediated biosynthetic pathway leading to the production of an ET-1[1-31] peptide, which was found to reproduce the ETA receptor-mediated vascular effects of ET-1[1-21] [17].
• Moreover, rMCP-4 hydrolyzed MeO-Suc-Arg-Ala-Tyr-pNA, thus verifying that this protease belongs to the chymase family. rMCP-4 bound to heparin, and the enzymatic activity toward MeO-Suc-Arg-Ala-Tyr-pNA was strongly enhanced in the presence of heparin [18].
• Neither phosphoramidon nor chymostatin, a chymase inhibitor, influenced the generation of DAG evoked by big ET-1 [19].

Analytical, diagnostic and therapeutic context of Mcpt1

• Southern blot analysis indicates that the rat vascular chymase is encoded by a separate gene [1].
• The chymase mRNA levels in the heart and other tissues were assessed by competitive reverse transcriptase-polymerase chain reaction (RT-PCR) [8].
• Chymase and angiotensin-converting enzyme (ACE) activities, and angiotensin II (Ang II) content in the heart were determined by radioimmunoassay (RIA) [8].
• Four weeks after ligation, echocardiography revealed that chymase inhibitor treatment reduced the akinetic area and increased fractional area change but did not significantly change left ventricular end-diastolic area [2].
• RX 77368-stimulated RMCP II release was also abolished by vagotomy and reduced by atropine by 65% [13].

References