Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.15.1 (ACE)
 18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Atrial natriuretic peptide (ANP) regulates a variety of physiological parameters, including the blood pressure and intravascular volume, by interacting with its receptors present on the plasma membrane. ANP receptors are of three subtypes: ANP-A, -B and -C receptors. ANP-A and ANP-B receptors are guanylyl cyclase receptors, whereas ANP-C receptors are coupled to adenylyl cyclase inhibition or phospholipase C activation through inhibitory guanine nucleotide-regulating protein. Unlike other G protein-coupled receptors, ANP-C receptors have a single transmembrane domain and a short cytoplasmic domain of 37 amino acids, the cytoplasmic domain has a structural specificity like those of other single-transmembrane-domain receptors and 37 amino-acid cytoplasmic domain peptide is able to exert is inhibitory effect on adenylyl cyclase. The activation of ANP-C receptor by C-ANP(4-23) (a ring-deleted peptide of ANP) and C-type natriuretic peptide inhibits the mitogen-activated protein kinase activity stimulated by endothelin-3, platelet-derived growth factor and phorbol-12 myristate 13-acetate. C-ANP also inhibits mitogen-induced stimulation of DNA synthesis, indicating that the ANP-C receptor plays a role in cell proliferation through an inhibition of mitogen-activated protein kinase and suggesting that the ANP-C receptor might also be coupled to other signal transduction mechanism(s) or that there might be an interaction of the ANP-C receptor with some other signalling pathways. ANP receptor binding is decreased in most organs in hypertensive subjects and hypertensive animals. This decrease is consistent with there being fewer guanylyl cyclase-coupled receptors in the kidney and vasculature and selective inhibition of the ANP-C receptor in the thymus and spleen. Platelet ANP-C receptors are decreased in number in hypertensive patients and spontaneously hypertensive rats. ANP-A, -B and -C receptors are decreased in number in deoxycorticosterone acetate-salt-treated kidneys and vasculature; however, the responsiveness of adenylyl cyclase to ANP is augmented in the vasculature and heart and is attenuated completely in platelets. These alterations in ANP receptor subtypes may be related to the pathophysiology of hypertension. Several hormones such as angiotensin II, ANP and catecholamines, the levels of which are increased in hypertension, downregulate or upregulate ANP-C receptors and ANP-C receptor-mediated inhibition of adenylyl cyclase. It can be suggested that the antihypertensive action of several types of drugs such as angiotensin converting enzyme inhibitors, angiotensin type 1 receptor antagonists and beta2-adrenergic antagonists may partly be attributed to their ability to modulate the expression and function of the ANP-C receptor.
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PMID:Atrial natriuretic peptide-C receptor and membrane signalling in hypertension. 928 Feb 3

In addition to cardiac myocyte hypertrophy, proliferation and increased extracellular matrix production of cardiac fibroblasts occur in response to cardiac overload. This remodeling of the cardiac interstitium is a major determinant of pathologic hypertrophy leading to ventricular dysfunction and heart failure. Atrial and brain natriuretic peptides (ANP and BNP) are cardiac hormones produced primarily by the atrium and ventricle, respectively. Plasma ANP and BNP concentrations are elevated in patients with hypertension, cardiac hypertrophy, and acute myocardial infarction, suggesting their pathophysiologic roles in these disorders. ANP and BNP exhibit diuretic, natriuretic, and vasodilatory activities via a guanylyl cyclase-coupled natriuretic peptide receptor subtype (guanylyl cyclase-A or GC-A). Here we report the generation of mice with targeted disruption of BNP (BNP-/- mice). We observed focal fibrotic lesions in ventricles from BNP-/- mice with a remarkable increase in ventricular mRNA expression of ANP, angiotensin converting enzyme (ACE), transforming growth factor (TGF)-beta3, and pro-alpha1(I) collagen [Col alpha1(I)], which are implicated in the generation and progression of ventricular fibrosis. Electron microscopic examination revealed supercontraction of sarcomeres and disorganized myofibrils in some ventricular myocytes from BNP-/- mice. No signs of cardiac hypertrophy and systemic hypertension were noted in BNP-/- mice. In response to acute cardiac pressure overload induced by aortic constriction, massive fibrotic lesions were found in all the BNP-/- mice examined, accompanied by further increase of mRNA expression of TGF-beta3 and Col alpha1(I). We postulate that BNP acts as a cardiocyte-derived antifibrotic factor in the ventricle.
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PMID:Brain natriuretic peptide appears to act locally as an antifibrotic factor in the heart. 1155 81

Myocardial hypertrophy and extended cardiac fibrosis are independent risk factors for congestive heart failure and sudden cardiac death. Before age 50, men are at greater risk for cardiovascular disease than age-matched women. In the current studies, we found that cardiac hypertrophy and fibrosis were significantly more pronounced in males compared with females of guanylyl cyclase-A knockout (GC-A KO) mice at 16 wk of age. These gender-related differences were not seen in wild-type mice. In the further studies, either castration (at 10 wk of age) or flutamide, an androgen receptor antagonist, markedly attenuated cardiac hypertrophy and fibrosis in male GC-A KO mice without blood pressure change. In contrast, ovariectomy (at 10 wk of age) had little effect. Also, chronic testosterone infusion increased cardiac mass and fibrosis in ovariectomized GC-A mice. None of the treatments affected cardiac mass or the extent of fibrosis in wild-type mice. Overexpression of mRNAs encoding atrial natriuretic peptide, brain natriuretic peptide, collagens I and III, TGF-beta1, TGF-beta3, angiotensinogen, and angiotensin converting enzyme in the ventricles of male GC-A KO mice was substantially decreased by castration. The gender differences were virtually abolished by targeted deletion of the angiotensin II type 1A receptor gene (AT1A). Neither castration nor testosterone administration induced any change in the cardiac phenotypes of double-KO mice for GC-A and AT1A. Thus, we suggest that androgens contribute to gender-related differences in cardiac hypertrophy and fibrosis by a mechanism involving AT1A receptors and GC-A.
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PMID:Androgen contributes to gender-related cardiac hypertrophy and fibrosis in mice lacking the gene encoding guanylyl cyclase-A. 1459 59

The objective of the present study was to assess the cardioprotective effect of dual NEP-ACE inhibition in relation to endogenous cardiac bradykinin (BK), its active metabolite des-Arg9-BK, endogenous brain natriuretic peptides (BNP), and cGMP. Rats were treated with the dual metallopeptidase inhibitor, omapatrilat, or the ACE inhibitor, ramipril, for 7 d (1 mg.kg(-1).d(-1)). Hearts were then isolated and subjected to a zero-flow ischemia and reperfusion (except controls), in the absence or presence of either a B2-receptor antagonist (Hoe-140), a B1-receptor antagonist (Lys-Leu8-des-Arg9-BK), or the GC-A/GC-B-receptor antagonist (HS-142-1). Chronic omapatrilat and ramipril increased the amount of endogenous BK collected upon reperfusion, but only ramipril increased that of des-Arg9-BK. Only omapatrilat increased both peak BNP and peak cGMP upon reperfusion, those increases being blocked by Hoe-140. Chronic omapatrilat (but not ramipril) decreased the total noradrenaline and lactate dehydrogenase release during the reperfusion period. Importantly, only omapatrilat improved the functional recovery of the ischemic reperfused heart, with a reduced left ventricular end-diastolic pressure, and improved developed left ventricular pressure. All cardio protective effects of omapatrilat were blocked by Hoe-140 and by HS-142-1, but not by the B1-receptor antagonist. In conclusion, a chronic treatment with a dual metallopeptidase inhibitor demonstrated a cardioprotective action not observed with an ACE inhibitor in a context of severe ischemia in rat isolated hearts, which was mediated by both endogenous BK and BNP.
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PMID:The cardioprotective effect of dual metallopeptidase inhibition: respective roles of endogenous kinins and natriuretic peptides. 1579 Dec 90

The objective of the present study was to determine whether targeted-disruption of Npr1 gene (encoding for guanylyl cyclase/natriuretic peptide receptor-A; GC-A/NPRA) upregulates pro(renin) receptor (P)RR expression and leads to the activation of MAPKs in Npr1 gene-knockout mice. The Npr1 homozygous (Npr1-/-; 0-copy), heterozygous (Npr1+/-; 1-copy), wild-type (Npr1+/+; 2-copy), and gene-duplicated (Npr1++/++; 4-copy) mice were utilized. To identify the canonical pathway of (P)RR, we administered ACE-1 inhibitor (captopril), AT1R blocker (losartan), and MAPKs inhibitors (U0126 and SB203580) to all Npr1 mice genotypes. The renal expression of (P)RR mRNA was increased by 3-fold in 0-copy mice and 2-fold in 1-copy mice compared with 2-copy mice, which was also associated with significantly increased expression of ACE-1 and AT1R mRNA levels. Similarly, the phosphorylation of MAPKs (Erk1/2 and p-p38) was enhanced by 3.5-fold and 3.2-fold, respectively, in 0-copy mice with significant increases in 1-copy mice compared with 2-copy mice. The kidney and plasma levels of proinflammatory cytokines were significantly elevated in 0-copy and 1-copy mice. Treatment with captopril and losartan did not alter the expression of (P)RR in any of the Npr1 mice genotypes. Interestingly, losartan significantly reduced the phosphorylation of Erk1/2 and p38 in Npr1 mice. The present results suggest that the ablation of Npr1 upregulates (P)RR, MAPKs (Erk1/2 and p38), and proinflammatory cytokines in 0-copy and 1-copy mice. In contrast, the duplication of Npr1 exhibits the anti-inflammatory and antihypertensive effects by reducing the activation of MAPKs and inhibiting the expression levels of RAAS components and proinflammatory cytokines.
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PMID:Genetic disruption of guanylyl cyclase/natriuretic peptide receptor-A upregulates renal (pro) renin receptor expression in Npr1 null mutant mice. 3096 84