Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin-converting enzyme (ACE) has a critical role in cardiovascular function by cleaving the carboxy terminal His-Leu dipeptide from angiotensin I to produce a potent vasopressor octapeptide, angiotensin II. Inhibitors of ACE are a first line of therapy for hypertension, heart failure, myocardial infarction and diabetic nephropathy. Notably, these inhibitors were developed without knowledge of the structure of human ACE, but were instead designed on the basis of an assumed mechanistic homology with carboxypeptidase A. Here we present the X-ray structure of human testicular ACE and its complex with one of the most widely used inhibitors, lisinopril (N2-[(S)-1-carboxy-3-phenylpropyl]-L-lysyl-L-proline; also known as Prinivil or Zestril), at 2.0 A resolution. Analysis of the three-dimensional structure of ACE shows that it bears little similarity to that of carboxypeptidase A, but instead resembles neurolysin and Pyrococcus furiosus carboxypeptidase--zinc metallopeptidases with no detectable sequence similarity to ACE. The structure provides an opportunity to design domain-selective ACE inhibitors that may exhibit new pharmacological profiles.
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PMID:Crystal structure of the human angiotensin-converting enzyme-lisinopril complex. 1254 Aug 54

A recent report indicated that hyperhomocysteinemia (Hhe), in addition to its atherothrombotic effects, exacerbates the adverse cardiac remodeling seen in response to hypertension, a powerful stimulus for pathological ventricular hypertrophy. The present study was undertaken to determine whether Hhe has a direct effect on ventricular remodeling and function in the absence of other hypertrophic stimuli. Male Wistar-Kyoto rats were fed either an amino acid-defined control diet or an intermediate Hhe-inducing diet. After 10 wk of dietary treatment, rats were subjected to echocardiographic assessment of left ventricular (LV) dimensions and systolic function. Subsequently, blood was collected for plasma homocysteine measurements, and the rats were killed for histomorphometric and biochemical assessment of cardiac remodeling and for in vitro cardiac function studies. Significant LV hypertrophy was detected by echocardiographic measurements, and in vitro results showed hypertrophy with significantly increased myocyte size in the LV and right ventricle (RV). LV and RV remodeling was characterized by a disproportionate increase in perivascular and interstitial collagen, coronary arteriolar wall thickening, and myocardial mast cell infiltration. In vitro study of LV function demonstrated abnormal diastolic function secondary to decreased compliance because the rate of relaxation did not differ between groups. LV systolic function did not vary between groups in vitro. In summary, in the absence of other hypertrophic stimuli short-term intermediate Hhe caused pathological hypertrophy and remodeling of both ventricles with diastolic dysfunction of the LV. These results demonstrate that Hhe has direct adverse effects on cardiac structure and function, which may represent a novel direct link between Hhe and cardiovascular morbidity and mortality, independent of other risk factors.
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PMID:Hyperhomocysteinemia leads to pathological ventricular hypertrophy in normotensive rats. 1273 62

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by exuberant inflammation and fibrosis, a process believed to contribute to progressive loss of normal renal function. Despite early-onset hypertension and intrarenal renin/angiotensin II (AngII) activation, angiotensin-converting enzyme (ACE) inhibition does not consistently confer renal protection in ADPKD. The hypothesis was that mast cells within the inflammatory interstitium release chymase, an enzyme capable of efficient conversion of AngI to AngII, providing an ACE-independent route of AngII generation. End-stage ADPKD renal tissue extracts and cyst fluids were assayed for time-dependent, chymostatin-inhibitable conversion of (125)I-AngI to (125)I-AngII under conditions of ACE and aminopeptidase inhibition by means of HPLC. Thirteen of 14 ADPKD kidney extracts exhibited chymase-like AngII-generating capacity; calculated initial reaction rates averaged 3.9 +/- 2.9 fmol AngII/min/ micro g protein with a mean maximal conversion of 55% +/- 30% of added substrate. AngII-generating activity was both protein and substrate dependent. All five cyst fluid samples were negative. Chymase-like activity was detectable in only three of six non-ADPKD kidney extracts. Immunoreactive chymase protein was present in/around mast cells within the fibrotic renal interstitium in all samples. Findings demonstrate for the first time the presence of mast cells, mast cell-associated immunoreactive chymase protein, and chymase-like AngII generating capacity in ADPKD cystic kidneys. Results support the potential for ACE-independent AngII generation and for mast cell-initiated inflammatory processes in ADPKD, each with therapeutic implications for ADPKD renal progression.
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PMID:Chymase-like angiotensin II-generating activity in end-stage human autosomal dominant polycystic kidney disease. 1474 98

Chymase is a chymotrypsin-like serine protease secreted from mast cells. Mammalian chymases are classified into two subgroups (alpha and beta) according to structure and substrate specificity; human chymase is an alpha-chymase. An important action of chymase is the ACE-independent conversion of Ang I to Ang II, but chymase also degrades the extracellular matrix, activates TGF-beta1 and IL-1beta, forms 31-amino acid endothelins and is involved in lipid metabolism. Under physiological conditions, the role of chymase in blood vessels is uncertain. In pathological situations, however, chymase may be important. In animal models of hypertension and atherosclerosis, chymase may be involved in lipid deposition and intimal and smooth muscle hyperplasia, at least in some vessels. In addition, chymase has pro-angiogenic properties. In human diseased blood vessels (e.g. atherosclerotic and aneurysmal aorta; remodeled pulmonary blood vessels), there are increases in chymase-containing mast cells and/or in chymase-dependent conversion of Ang I to Ang II. These findings have raised the possibility that inhibition of chymase may have a role in the therapy of vascular disease. The effects of chymase can theoretically be attenuated either by reducing availability of the enzyme, with a mast cell stabiliser, or alternatively with specific chymase inhibitors. The mast cell stabiliser, tranilast, was shown to be beneficial in animal models of atherosclerosis, where a prevention protocol was used, but was not effective in clinical trials where it was administered after angioplasty. Chymase inhibitors could have the advantage of being effective even if used after injury. Several orally active inhibitors, including SUN-C8257, BCEAB, NK3201 and TEI-E548, are now available. These have yet to be tested in humans, but promising results have been obtained in animal models of atherosclerosis and angiogenesis. It is concluded that orally active inhibitors of chymase may have a place in the treatment of vascular diseases where injury-induced mast cell degranulation contributes to the pathology.
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PMID:Vascular chymase: pathophysiological role and therapeutic potential of inhibition. 1498 62

Several studies have examined the role of mast cells in the myocardial response to injury such as that caused by hypertension and ischemia-reperfusion. However, little is known about the influence of mast cells on normal myocardial structure and function. The present experiments examined cardiac function in Langendorff-perfused hearts isolated from 6- and 9-mo-old male mast cell-deficient (Ws/Ws) and mast cell-competent rats. A fluid-filled balloon catheter was used to measure left ventricular diastolic and systolic function at increasing preload volumes. At 6 mo of age, mast cell-deficient rats showed a slight cardiac hypertrophy (as monitored by heart weight and heart weight-to-body weight ratio) but no significant change in maximum observed systolic or diastolic function. In contrast, at 9 mo of age, the mast cell-deficient group showed no signs of hypertrophy but displayed a diastolic dysfunction characterized by decreased compliance without a significant decline in maximum observed basal -dP/dtmax. There were no significant differences in maximum observed values for measures of systolic function (developed pressure and +dP/dtmax). In summary, the results of this study in adult rats suggest that mast cells influence cardiac function in the absence of injury and that observed differences between mast cell-competent and -deficient animals vary with age. Thus it is important to consider these "physiological" actions and resulting changes in function when studying effects of insult in mast cell-deficient models.
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PMID:Cardiac function in hearts isolated from a rat model deficient in mast cells. 1538 1

The renin-angiotensin system is a key target for drugs combating cardiovascular disease. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor type-1 (AT1 receptor) blockers are well known. However, angiotensin peptides can be generated through a number of pathways besides the classic system. This review outlines some of these pathways, their relation to the classic system and the likely effect of inhibiting them. Renin is still the key enzyme in angiotensin peptide generation and seems to be the only route to angiotensin I formation in vivo. Renin inhibitors may have some advantages in terms of specificity. Also, by blocking angiotensin I generation, the production of downstream bioactive angiotensin I metabolites should also be blocked. Chymase, a mast cell serine protease, cleaves angiotensin I to produce angiotensin II and may be important at sites of inflammation such as atherosclerotic plaque. Angiotensin-converting enzyme 2 (ACE2), a carboxypeptidase structurally related to ACE but resistant to ACE inhibitors, has a protective effect on cardiac function. Neutral endopeptidase 24.11 breaks down both atrial natriuretic peptide and angiotensin II. Inhibiting it potentiates the action of endogenous atrial peptide but only affects circulating angiotensin II when basal levels are above normal. Dual inhibitors of ACE and endopeptidase 24.11 may be of value where there is both sodium retention and increased angiotensin II. Targeting the renin-angiotensin system by gene therapy or antibody treatment may provide a longer-term treatment for hypertension.
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PMID:Targeting the renin-angiotensin system: what's new? 1563 41

Postural tachycardia syndrome (POTS) is a disabling condition that commonly affects otherwise normal young females. Because these patients can present with a flushing disorder, we hypothesized that mast cell activation (MCA) can contribute to its pathogenesis. Here we describe POTS patients with MCA (MCA+POTS), diagnosed by episodes of flushing and abnormal increases in urine methylhistamine, and compared them to POTS patients with episodic flushing but normal urine methylhistamine and to normal healthy age-matched female controls. MCA+POTS patients were characterized by episodes of flushing, shortness of breath, headache, lightheadedness, excessive diuresis, and gastrointestinal symptoms such as diarrhea, nausea, and vomiting. Triggering events include long-term standing, exercise, premenstrual cycle, meals, and sexual intercourse. In addition, patients were disabled by orthostatic intolerance and a characteristic hyperadrenergic response to posture, with orthostatic tachycardia (from 79+/-4 to 114+/-6 bpm), increased systolic blood pressure on standing (from 117+/-5 to 126+/-7 mm Hg versus no change in POTS controls), increased systolic blood pressure at the end of phase II of the Valsalva maneuver (157+/-12 versus 117+/-9 in normal controls and 119+/-7 mm Hg in POTS; P=0.048), and an exaggerated phase IV blood pressure overshoot (50+/-10 versus 17+/-3 mm Hg in normal controls; P<0.05). In conclusion, MCA should be considered in patients with POTS presenting with flushing. These patients often present with a typical hyperadrenergic response, but beta-blockers should be used with great caution, if at all, and treatment directed against mast cell mediators may be required.
Hypertension 2005 Mar
PMID:Hyperadrenergic postural tachycardia syndrome in mast cell activation disorders. 1571 Jul 81

Chymase degrades angiotensin I (AI) to form angiotensin II (AII), probably constituting a bypass of the renin-angiotensin cascade. Chymase activity increases in some vascular diseases. In the kidney, an increase in chymase activity was reported in an animal model of ischemic kidney of renovascular hypertension (RVH); however, no such evidence has been provided in humans. We treated a 64-year-old patient with severe unilateral RVH and atherosclerosis, for whom removal of the ischemic kidney was the only option. Using immunohistochemical staining, we investigated chymase activity in the removed kidney and associated artery and vein. An increase in chymase activity, together with mast cells infiltrating the interstitium, was observed where interstitial fibrosis was seen. In the renal artery, where severe atherosclerosis was seen, and also in the vein, mast cell infiltration in the adventitia was accompanied by chymase. The captopril test showed an increase in serum aldosterone level, with a concomitant increase in plasma renin activity and decrease in blood pressure. Because the decrease in blood pressure implies a decrease in circulatory AII levels, it is plausible that in this patient, chymase had a role in AII formation in the adrenal gland to stimulate aldosterone secretion. Thus, by means of captopril, AI levels increased, and chymase may have produced AII in loci tissues, which, in turn, stimulated aldosterone secretion. This is the first report of an increase in chymase activity in the interstitium of an ischemic kidney and renal artery and vein in a patient with RVH and atherosclerosis.
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PMID:Mast cell chymase in the ischemic kidney of severe unilateral renovascular hypertension. 1575 63

The chronic elevation in ventricular wall stress secondary to ventricular volume or pressure overload leads to structural remodeling of the muscular, vascular and extracellular matrix components of the myocardium. While initially a compensatory response, the progressive hypertrophy and ventricular dilatation induced by this condition ultimately have a detrimental effect on ventricular function, resulting in heart failure. Fibrillar collagen provides the skeletal framework which interconnects the cardiomyocytes, thereby maintaining ventricular shape and size and contributing to tissue stiffness. Accordingly, these myocardial collagen fibers must be disrupted for ventricular dilatation, sphericalization and wall thinning to occur. The presence of an abundant, latent matrix metalloproteinase (MMP) population which coexists with myocardial fibrillar collagen has been documented. Thus, the potential for collagen degradation to exceed synthesis exists should there be significant activation of this latent MMP system. Mast cells are known to store and release a variety of biologically active mediators including TNF-alpha and proteases such as tryptase and chymase, which can induce MMP activation. Increased cardiac mast cell density has been implicated in the pathophysiology of human end-stage cardiomyopathy and experimental myocardial infarction, hypertension and chronic volume overload secondary to mitral regurgitation and aorto-caval fistula. The potential role of cardiac mast cells in activating MMPs, which then results in fibrillar collagen degradation and adverse myocardial remodeling secondary to chronic volume and pressure overload will be the subject of this review.
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PMID:Cardiac mast cell regulation of matrix metalloproteinase-related ventricular remodeling in chronic pressure or volume overload. 1637 24

The concerted activation of leukocytes and vessels shapes multiple physiological and pathological responses. A large number of these processes shares a common signal transduction platform involving the activation of plasma membrane bound G protein-coupled receptors (GPCRs). This event is usually amplified by the production of different intra-cellular second messenger molecules. Among these mediators, the phosphorylated lipid phosphatidylinositol (3,4,5)-trisphosphate (PIP3) produced by phosphoinositide 3-kinase gamma (PI3Kgamma) has recently emerged as a crucial signal in both vascular and white blood cells. The generation of mice lacking PI3Kgamma showed that the GPCR/PI3Kgamma/PIP3 signaling pathway controls diverse immune modulatory and vascular functions like respiratory burst, cell recruitment, mast cell reactivity, platelet aggregation, endothelial activation as well as smooth muscle contractility. The relative specificity of these events suggests that blocking PI3Kgamma function might turn out beneficial for diseases like inflammation, allergy, thrombosis, and major cardiovascular disorders like hypertension, thus offering a wide range of therapeutic opportunities.
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PMID:Signaling through PI3Kgamma: a common platform for leukocyte, platelet and cardiovascular stress sensing. 1654 58


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