Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human alpha-chymase is an efficient angiotensin (AT) converting enzyme, selectively hydrolyzing AT I at Phe8 to generate bioactive AT II, which can promote cardiac hypertrophy, vascular stenosis, and hypertension. Some related enzymes, such as rat beta-chymase 1, are much less selective, destroying AT by cleaving at Tyr4. Comparisons of chymase structure and activity led to speculation that interaction between AT and the side chain of Lys40 or Arg143 accounts for the human enzyme's marked preference for Phe8 over Tyr4. To test these hypotheses, we compared AT hydrolysis by wild-type chymase with that by mutants changing Lys40 or Arg143 to neutral residues. Lys40 was exchanged for alanine, the residue found in canine alpha- and rat beta-chymase 1, the latter being dramatically less selective for hydrolysis at Phe8. Arg143 was exchanged for glutamine found in rat beta-chymase 1. The Lys40Ala mutant is a dog-like enzyme retaining strong preference for Phe8 but with Tyr4 hydrolytic rates enhanced 16-fold compared to wild-type human enzyme. Thus, of 40 residues mismatched between dog and human enzymes, a single residue accounts for most of the difference in specificity between them. The Arg143Gln mutant, contrary to prediction, remains highly Phe8-selective. Therefore, Lys40, but not Arg143, contributes to human chymase's remarkable preference for AT II generation over destruction.
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PMID:Lys40 but not Arg143 influences selectivity of angiotensin conversion by human alpha-chymase. 1200 14

Human heart tissue enzymes cleave angiotensin (Ang) I to release Ang 1-9, Ang II, or Ang 1-7. In atrial homogenate preparations, cathepsin A (deamidase) is responsible for 65% of the liberated Ang 1-9. Ang 1-7 was released (88% to 100%) by a metallopeptidase, as established with peptidase inhibitors. Ang II was liberated to about equal degrees by ACE and chymase-type enzymes. Cathepsin A's presence in heart tissue was also proven because it deamidated enkephalinamide substrate by immunoprecipitation of cathepsin A with antiserum to human recombinant enzyme and by immunohistochemistry. In immunohistochemistry, cathepsin A was detected in myocytes of atrial tissue. The products of Ang I cleavage, Ang 1-9 and Ang 1-7, potentiated the effect of an ACE-resistant bradykinin analog and enhanced kinin effect on the B(2) receptor in Chinese hamster ovary cells transfected to express human ACE and B(2) (CHO/AB), and in human pulmonary arterial endothelial cells. Ang 1-9 and 1-7 augmented arachidonic acid and nitric oxide (NO) release by kinin. Direct assay of NO liberation by bradykinin from endothelial cells was potentiated at 10 nmol/L concentration, 2.4-fold (Ang 1-9) and 2.1-fold (Ang 1-7); in higher concentrations, Ang 1-9 was significantly more active than Ang 1-7. Both peptides had traces of activity in the absence of bradykinin. Ang 1-9 and Ang 1-7 potentiated bradykinin action on the B(2) receptor by raising arachidonic acid and NO release at much lower concentrations than their 50% inhibition concentrations (IC(50)s) with ACE. They probably induce conformational changes in the ACE/B(2) receptor complex via interaction with ACE.
Hypertension 2002 May
PMID:Angiotensin 1-9 and 1-7 release in human heart: role of cathepsin A. 1201 79

Two enzymes, chymase and angiotensin converting enzyme (ACE), are involved in the production of angiotensin II. Our previous study revealed the male-specific effect of the ACE DD genotype on the risk for hypertension, but the genetic role of chymase remains unclear. In the present study, we report the results of an association study involving 1,046 subjects recruited from a general population in Ohasama, a rural community in the northern part of Japan. In addition to casual blood pressure (casual BP) measurement, home BP measurements were obtained from all participants. There were no differences in either home or casual BP values according to G3255A polymorphism of the mast cell chymase gene (MCC). HDL cholesterol level was significantly higher among carriers of the A3255 allele (p<0.04). After adjustment for confounding factors, the A3255 allele was still shown to have an effect on HDL cholesterol metabolism (p<0.03). Multiple regression analysis showed that MCC polymorphism was significantly and independently related to serum HDL cholesterol level. In conclusion, G3255A polymorphism of MCC is not directly associated with blood pressure but may modulate the prevalence of hypertensive complications via alteration of lipid metabolism.
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PMID:Association of a mast cell chymase gene variant with HDL cholesterol, but not with blood pressure in the Ohasama study. 1204 32

The present study was undertaken to clarify the role of intrarenal angiotensin (Ang) II and its generating pathways in clipped and nonclipped kidneys of 4-week unilateral renal artery stenosis in anesthetized dogs. After 4 weeks, renal plasma flow (RPF) decreased in clipped and nonclipped kidneys (baseline, 59+/-3; clipped, 16+/-1; nonclipped, 44+/-2 mL/min; P<0.01, n=22). Renal Ang I levels increased only in clipped, whereas intrarenal Ang II contents were elevated in both clipped (from 0.7+/-0.1 to 2.0+/-0.2 pg/mg tissue) and nonclipped kidneys (from 0.6+/-0.1 to 2.5+/-0.3 pg/mg tissue). Intrarenal ACE activity was increased in nonclipped kidneys but was unaltered in clipped kidneys. An angiotensin receptor antagonist (olmesartan medoxomil) given into the renal artery markedly restored RPF, and dilated both afferent and efferent arterioles (using intravital videomicroscopy). Furthermore, in clipped kidneys, the elevated Ang II was suppressed by a chymase inhibitor, chymostatin (from 2.1+/-0.6 to 0.8+/-0.1 pg/mg tissue; P<0.05), but not by cilazaprilat. In nonclipped kidneys, in contrast, cilazaprilat, but not chymostatin, potently inhibited the intrarenal Ang II generation (from 2.4+/-0.3 to 1.5+/-0.2 pg/mg tissue; P<0.05). Finally, [Pro11-D-Ala12]Ang I (an inactive precursor that yields Ang II by chymase but not by ACE; 1 to 50 nmol/kg) markedly elevated intrarenal Ang II in clipped, but not in nonclipped, kidneys. In conclusion, renal Ang II contents were elevated in both clipped and nonclipped kidneys, which contributed to the altered renal hemodynamics and microvascular tone. Furthermore, the mechanisms for intrarenal Ang II generation differ, and chymase activity is enhanced in clipped kidneys, whereas ACE-mediated Ang II generation is possibly responsible for elevated Ang II contents in nonclipped kidneys.
Hypertension 2002 Jul
PMID:Differential regulation of elevated renal angiotensin II in chronic renal ischemia. 1210 35

Inhibition of angiotensin II action or its formation by angiotensin-converting enzyme has been highly successful in the treatment of cardiovascular diseases. Since the identification of chymase as a major angiotensin II-forming enzyme in the human heart and its vessels more than a decade ago, numerous studies have sought to understand the importance of this enzyme in tissue angiotensin II formation and in the pathogenesis of hypertension, congestive heart failure, and vascular disease. Recent studies show that chymase and angiotensin-converting enzyme regulate angiotensin II production in distinct tissue compartments and that, in the pathogenesis of cardiovascular diseases, chymase-dependent effects extend beyond its ability to regulate tissue angiotensin II levels.
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PMID:Dissecting the role of chymase in angiotensin II formation and heart and blood vessel diseases. 1215 72

Human chymase is a protease involved in physiological processes ranging from inflammation to hypertension. As are all proteases of the trypsin fold, chymase is synthesized as an inactive "zymogen" with an N-terminal pro region that prevents the transition of the zymogen to an activated conformation. The 1.8 A structure of pro-chymase, reported here, is the first zymogen with a dipeptide pro region (glycine-glutamate) to be characterized at atomic resolution. Three segments of the pro-chymase structure differ from that of the activated enzyme: the N-terminus (Gly14-Gly19), the autolysis loop (Gly142-Thr154), and the 180s loop (Pro185A-Asp194). The four N-terminal residues (Gly14-Glu15-Ile16-Ile17) are disordered. The autolysis loop occupies a position up to 10 A closer to the active site than is seen in the activated enzyme, thereby forming a hydrogen bond with the catalytic residue Ser195 and occluding the S1' binding pocket. Nevertheless, the catalytic triad (Asp102-His57-Ser195) is arrayed in a geometry close to that seen in activated chymase (all atom rmsd of 0.52 A). The 180s loop of pro-chymase is, on average, 4 A removed from its conformation in the activated enzyme. This conformation disconnects the oxyanion hole (the amides of Gly193 and Ser195) from the active site and positions only approximately 35% of the S1-S3 binding pockets in the active conformation. The backbone of residue Asp194 is rotated 180 degrees when compared to its conformation in the activated enzyme, allowing a hydrogen bond between the main-chain amide of residue Trp141 and the carboxylate of Asp194. The side chains of residues Phe191 and Lys192 of pro-chymase fill the Ile16 binding pocket and the base of the S1 binding pocket, respectively. The zymogen positioning of both the 180s and autolysis loops are synergistic structural elements that appear to prevent premature proteolysis by chymase and, quite possibly, by other dipeptide zymogens.
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PMID:Structure of human pro-chymase: a model for the activating transition of granule-associated proteases. 1261 56

To seek evidence that the nonhuman primate arterial wall, as it ages in the absence of atherosclerosis, exhibits alterations in pathways that are involved in the pathogenesis of experimental atherosclerosis, we assessed aortic matrix metalloproteinase-2 (MMP-2) and its regulators, ie, membrane type-1 of matrix metalloproteinase (MT1-MMP) and tissue inhibitor of matrix metalloproteinase-2 (TIMP-2), and the expression of angiotensin II (Ang II), angiotensin-converting enzyme (ACE), and chymase in young (6.4+/-0.7 years) and old (20.0+/-1.9 years) male monkeys. With advancing age, (1) the intimal thickness increased 3-fold and contained numerous vascular smooth muscle cells and matrix, but no inflammatory cells; (2) the intimal MMP-2 antibody-staining fraction increased by 80% (P<0.01); (3) in situ zymography showed that MMP-2 activity, mainly confined to the intima, increased 3-fold (P<0.01); (4) the MT1-MMP antibody-staining fraction increased by 150% (P<0.001), but the TIMP-2 antibody-staining fraction did not significantly change; (5) steady levels of the mRNA-staining fraction (via in situ hybridization) for MMP-2 increased 7-fold, for MT1-MMP increased 9-fold, and for TIMP-2 increased 2-fold (all P<0.001); and (6) intimal Ang II and ACE immunofluorescence were increased 5-fold and 5.6-fold, respectively, and colocalized with MMP-2. Thus, age-associated arterial remodeling and the development and progression of experimental atherosclerosis in young animals share common mechanisms, ie, MMP-2 activation and increased Ang II signaling. This might explain, in part, the dramatically exaggerated prevalence and severity of vascular diseases with aging.
Hypertension 2003 Jun
PMID:Aging increases aortic MMP-2 activity and angiotensin II in nonhuman primates. 1274 15

Angiotensin II (AngII) has been shown to play a critical role in diabetic nephropathy and vasculopathy. Although it is well recognized that an angiotensin-converting enzyme (ACE)-dependent AngII-generating system is a major source of intrarenal AngII production, it is here reported that the chymase-dependent AngII-generating system is upregulated in the human diabetic kidney. This becomes particularly strong in those with hypertension. In the normal kidney, while ACE was constitutively expressed by most kidney cells, chymase was weakly expressed by mesangial cells (MC) and vascular smooth muscle cells (VSMC) only. In the diabetic kidney, while ACE expression was significantly upregulated (1 to 3-fold) by tubular epithelial cells (TEC) and infiltrating mononuclear cells, there was also markedly increased chymase expression (10 to 15-fold) by both MC and VSMC, with strong deposition in the collagen-rich extracellular matrix including both diffuse and nodular glomerulosclerosis, tubulointerstitial fibrosis, and vascular sclerosis. Interestingly, while ACE expression showed no difference in patients with or without hypertension, upregulation of chymase in hypertensive patients was much stronger than that seen in those without hypertension (4 to 7-fold, P < 0.001). Correlation analysis showed that, in contrast to the ACE expression, upregulation of chymase correlated significantly with the increase in BP and the severity of collagen matrix deposition within the glomerulus, tubulointerstitium, and arterial walls (all with P < 0.001). In conclusion, the present study demonstrates that chymase, as an alternative AngII-generating enzyme, is markedly upregulated in the diabetic kidney and may be associated with the development of diabetic/hypertensive nephropathy. In addition, differential expression of ACE and chymase in the diabetic kidney indicates that both ACE and chymase may be of equal importance for AngII-mediated diabetic nephropathy and vascular disease. Results from this study suggest that blockade of both AngII-generating pathways may provide additional beneficial effect on diabetic nephropathy.
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PMID:Chymase is upregulated in diabetic nephropathy: implications for an alternative pathway of angiotensin II-mediated diabetic renal and vascular disease. 1281 57

A number of in vitro studies have suggested potential pathophysiological roles of human (h-) chymase. However, the lack of an appropriate animal model has left the in vivo roles of chymase unclear. To approach this problem, a transgenic mouse (TGM) model carrying the h-chymase gene was established. The h-chymase cDNA transgene was constructed with the chicken beta actin promoter and cytomegalovirus immediate early gene enhancer, and injected into mouse oocytes. Homozygous mice with a high copy number of the h-chymase gene suffered from intrauterine death. In three heterozygous TGM lines, h-chymase transgene expression was detected in entire organs, including the heart, vessels, skin, liver, lung, and brain. The h-chymase immunoreactivity was localized in the extracellular matrices of each organ, especially on the basement membranes of vessels. Aortic and hepatic chymase-dependent angiotensin II formations were significantly higher than those in the wild-type littermates. Three independent TGM lines showed the same phenotypic changes: elevation of blood pressure, left ventricular hypertrophy, emaciation with reduction in the lipid tissue, leukocytosis, and oligotrichia. The angiotensin II subtype 1 (AT1) receptor antagonist valsartan suppressed the elevated blood pressure completely and left ventricular hypertrophy incompletely, but did not affect the other phenotypes. These data suggested that in vivo expression of h-chymase caused mild hypertension (AT1 receptor-dependent) with left ventricular hypertrophy (partially AT1 receptor-dependent), and also chronic inflammatory changes (AT1 receptor-independent).
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PMID:Human chymase expression in a mice induces mild hypertension with left ventricular hypertrophy. 1462 Sep 33

Angiotensin II induces the organ derangements is not generated by the so-called classic rennin-angiotensin system but by the tissue angiotensin II generating system. We have confirmed this evidences by using different types of animal models such as hypertension, arteriosclerosis, vascular narrowing by balloon injury and in vein graft disease. In addition, we found that the ACE and chymase activities are increased in human aneurismal aorta. ACE inhibitor is effective to protect the development of hypertension and arteriosclerosis, but not to other models because the angiotensin II produced by chymase is involved in such diseases. Angiotensin II produced separately by ACE and chymase, participates independently in the development of vascular derangements.
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PMID:[Angiotensin II in organ organopathy]. 1473 31


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