Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stored cardiac pro-atrial natriuretic peptide (pro-ANP) is converted to ANP and released upon stretch from the atria into the circulation. Corin is a serin protease with pro-ANP-converting properties and may be the rate-limiting enzyme in ANP release. This study was aimed to clone and sequence corin in the rat and to analyze corin mRNA expression in heart failure when ANP release upon stretch is blunted. Full-length cDNA of rat corin was obtained from atrial RNA by RT-PCR and sequenced. Tissue distribution as well as regulation of corin mRNA expression in the atria were determined by RT-PCR and RNase protection assay. Heart failure was induced by an infrarenal aortocaval shunt. Stretch was applied to the left atrium in a working heart modus, and ANP was measured in the perfusates. The sequence of rat corin cDNA was found to be 93.6% homologous to mouse corin cDNA. Corin mRNA was expressed almost exclusively in the heart with highest concentrations in both atria. The aortocaval shunt led to cardiac hypertrophy and heart failure. Stretch-induced ANP release was blunted in shunt animals (control 1,195 +/- 197 fmol.min(-1).g(-1); shunt: 639 +/- 99 fmol.min(-1).g(-1), P < 0.05). Corin mRNA expression was decreased in both atria in shunt animals [right atrium: control 0.638 +/- 0.004 arbitrary units (AU), shunt 0.566 +/- 0.014 AU, P < 0.001; left atrium: control 0.564 +/- 0.009 AU, shunt 0.464 +/- 0.009 AU, P < 0.001]. Downregulation of atrial corin mRNA expression may be a novel mechanism for the blunted ANP release in heart failure.
 ...
PMID:Rat corin gene: molecular cloning and reduced expression in experimental heart failure. 1515 64

High levels of plasma atrial natriuretic peptides (ANP) are associated with pathological conditions such as congestive heart failure (CHF). Recently, we have identified a cardiac serine protease, corin, that is the pro-ANP convertase. In this study, we examined the regulation of corin gene expression in cultured hypertrophic cardiomyocytes and in the left ventricular (LV) myocardium of a rat model of heart failure. Quantitative RT-PCR analysis showed that both corin and ANP mRNA levels were significantly increased in phenylephrine (PE)-stimulated rat neonatal cardiomyocytes in culture. The increase in corin mRNA correlated closely with the increase in cell size and ANP mRNA expression in the PE-treated cells (r = 0.95, P < 0.01; r = 0.92, P < 0.01, respectively). The PE-treated cardiomyocytes had an increased activity in converting recombinant human pro-ANP to biologically active ANP, as determined by a pro-ANP processing assay and a cell-based cGMP assay. In a rat model of heart failure induced by ligation of the left coronary artery, corin mRNA expression in the noninfarcted LV myocardium was significantly higher than that of control heart tissues from sham-operated animals, when examined by Northern blot analysis and RT-PCR at 8 wk. These results indicate that the corin gene is upregulated in hypertrophic cardiomyocytes and failing myocardium. Increased corin expression may contribute to elevation of ANP in the setting of cardiac hypertrophy and heart failure.
 ...
PMID:Upregulation of corin gene expression in hypertrophic cardiomyocytes and failing myocardium. 1519 94

The serine proteases of the trypsin superfamily are versatile enzymes involved in a variety of biological processes. In the cardiovascular system, the importance of these enzymes in blood coagulation, platelet activation, fibrinolysis, and thrombosis has been well established. Recent studies have shown that trypin-like serine proteases are also important in maintaining cardiac function and contribute to heart-related disease processes. In this review, we describe the biological function of corin, tissue kallikrein, chymase and urokinase and discuss their roles in cardiovascular diseases such as hypertension, cardiac hypertrophy, heart failure, and aneurysm.
 ...
PMID:Serine proteases and cardiac function. 1605 20

B-type natriuretic peptide (BNP) has emerged as a reliable biomarker in patients with congestive heart failure. The mature, biologically active B-type natriuretic peptide, BNP(1-32), is cleaved by corin from the 108 amino acid proBNP. However, in vivo as well as in vitro data demonstrated that this BNP(1-32) might be an ideal substrate for the endogenous aminopeptidase, dipeptidyl-peptidase IV (DPP IV). DPP IV removes the two amino terminal amino acids (Ser Pro) from BNP(1-32) to produce BNP(3-32), which has been detected in plasma of patients with congestive heart failure. The biological effects of BNP(3-32) remain undetermined. In cultured human cardiomyocytes and fibroblasts, equimolar concentrations of BNP(1-32) and BNP(3-32) both exert similar biological effects, as evidenced by their cGMP (cyclic guanylate monophosphate) generating capacity. However, in a canine model, intravenous BNP(3-32) infusion resulted in less natriuresis, diuresis, and vasodilation compared to intravenous infusion of BNP(1-32). The clinical relevance of these observations might be important for patients in whom the plasma BNP concentrations, measured by commercially available immunoassays, are high. Further studies exploring whether DPP IV inhibitors increase the bioavailability of BNP(1-32), delay the progression of heart failure, and increase the efficacy of exogenous administration of BNP(1-32) in decompensated heart failure are needed.
 ...
PMID:Dipeptidyl-peptidase IV and B-type natriuretic peptide. From bench to bedside. 1932 4

The mature, biologically active 32-amino acid long B-type natriuretic peptide (BNP(1-32)), is cleaved by corin from the BNP prohormone. Recent data demonstrated that BNP(1-32) might be an ideal substrate for the endogenous aminopeptidase, dipeptidyl-peptidase (DPP) IV. DPP IV removes the two amino-terminal amino acids (Ser and Pro) from BNP(1-32) to produce BNP(3-32), which has been detected in plasma of patients with heart failure. In a canine model, intravenous BNP(3-32) infusion resulted in less natriuresis, diuresis and vasodilation compared to intravenous infusion of BNP(1-32). The clinical relevance of these observations may be important for patients with high plasma BNP concentrations, which can be measured by commercially available immunoassays. Further studies are needed to explore whether DPP IV inhibitors increase the bioavailability of BNP(1-32), delay the progression of heart failure and increase the efficacy of exogenously administered BNP(1-32) in decompensated heart failure.
 ...
PMID:B-type natriuretic peptide as a marker of heart failure: new insights from biochemistry and clinical implications. 2040 72

Atrial and brain natriuretic peptides (ANP and BNP) regulate blood pressure and cardiac function. In patients with heart failure (HF), plasma levels of pro-ANP and pro-BNP, the precursor forms of ANP and BNP, are highly elevated, but the mechanism underlying the apparent deficiency in natriuretic peptide processing is unclear. Corin is a cardiac protease that activates natriuretic peptides. In this study, we examined corin protein expression and activity in mouse and human failing hearts. Tissue samples were obtained from a mouse model of HF induced by myotrophin overexpression and from human nonfailing, hypertrophic, and failing hearts. Corin protein levels in the membrane fraction and tissue lysate were measured by Western blotting and ELISA. Corin catalytic and biological activities were measured by fluorescent substrate and pro-ANP processing assays. In mice, corin protein levels did not change with age in normal hearts but increased significantly in failing hearts. In humans, corin protein levels were similar in the atrium from nonfailing and failing hearts but were increased in the ventricle in failing hearts compared with those in nonfailing or hypertrophic hearts. Unlike the protein level, however, corin activity did not increase in failing hearts, as measured by fluorogenic substrate and pro-ANP processing assays. Our results indicate that corin activation is a rate-limiting step in failing hearts. Insufficient corin activation is expected to prevent natriuretic peptide processing and may contribute to body fluid retention and impaired cardiac function in patients with HF.
 ...
PMID:Protease corin expression and activity in failing hearts. 2080 29

B-type natriuretic peptide (BNP) and its related peptides are biomarkers for the diagnosis of heart failure. Recent studies identified several O-glycosylation sites, including Thr-71, on human pro-BNP but the functional significance was unclear. In this study, we analyzed glycosylation and proteolytic processing of pro-BNP in cardiomyocytes. Human pro-BNP wild-type (WT) and mutants were expressed in HEK 293 cells and murine HL-1 cardiomyocytes. Pro-BNP and BNP were analyzed by immunoprecipitation and Western blotting. Glycosidases and glycosylation inhibitors were used to examine carbohydrates on pro-BNP. The effects of furin and corin expression on pro-BNP processing in cells also were examined. We found that in HEK 293 cells, recombinant pro-BNP contained significant amounts of O-glycans with terminal oligosialic acids. Mutation at Thr-71 reduced O-glycans on pro-BNP and increased pro-BNP processing. In HL-1 cardiomyocytes, residue Thr-71 contained little O-glycans, and pro-BNP WT and T71A mutant were processed similarly. In HEK 293 cells, pro-BNP was processed by furin. Mutations at Arg-73 and Arg-76, but not Lys-79, prevented pro-BNP processing. In HL-1 cardiomyocytes, which express furin and corin, single or double mutations at Arg-73, Arg-76 and Lys-79 did not prevent pro-BNP processing. Only when all these three residues were mutated, was pro-BNP processing completely blocked. Our data indicate that pro-BNP glycosylation in cardiomyocytes differed significantly from that in HEK 293 cells. In HEK 293 cells, furin cleaved pro-BNP at Arg-76 whereas in cardiomyocytes corin cleaved pro-BNP at multiple residues including Arg-73, Arg-76 and Lys-79.
 ...
PMID:Glycosylation and processing of pro-B-type natriuretic peptide in cardiomyocytes. 2176 78

Corin is a transmembrane serine protease identified in the heart, where it converts natriuretic peptides from inactive precursors to mature active forms. Studies in animal models and patients with hypertension and heart disease demonstrate that corin is critical in maintaining normal blood pressure and cardiac function. Like many proteolytic enzymes, corin expression and activity are regulated. Cell biology experiments indicate that transcriptional control, intracellular protein trafficking, cell surface targeting, zymogen activation and ectodomain shedding are important mechanisms in regulating corin expression and activity in the heart. More recently, soluble corin was detected in human blood and its levels were found to be reduced in patients with heart failure (HF). These findings indicate that corin deficiency may be involved in the pathogenesis of HF and suggest that soluble corin may be used as a biomarker for the disease. In this review, we describe the function and regulation of corin and discuss recent studies of soluble corin in human blood and its potential use as a biomarker for HF.
 ...
PMID:Corin in clinical laboratory diagnostics. 2209 42

B-type natriuretic peptide (BNP) is a plasma marker of left ventricular dysfunction and cardiac volume overload. Currently it is mainly used in the cardiovascular field. BNP is an intrinsic regulator of the embryonic stem cell proliferation, and the reduction in BNP can increase the apoptosis rate. The epitope of N terminal pro-brain natriuretic peptide-BNP is most stable. BNP1-32 has the strongest biological activity but with lower plasma level in heart failure patients. The plasma BNP level plays an important role in the diagnosis, prognosis, hospital admission and mortality of heart failure, and can be used as a monitoring indicator in the treatment of heart failure. The deficiency of corin enzyme in patients with heart failure can cause the increase of cracking pro-BNP. BNP can also provide diagnostic and prognostic information for other populations and diseases. Genetic studies on BNP and its receptors also provide important information. Nesiritide, neutral endopeptidase inhibitors, and vasopeptidase inhibitors of the natriuretic peptide synthesis have been used for the treatment of cardiovascular disorders. However, more reliable and accurate approaches for detecting BNP and N terminal pro-brain natriuretic peptide-BNP require further investigations.
 ...
PMID:[Research advances in B-type natriuretic peptide and its clinical application in the patients with cardiovascular diseases]. 2277 7

Recent studies reported that many different biochemical forms of B-type-related peptides circulate in human blood. In particular, a significant amount of the prohormone peptide (i.e., proBNP108) can be detected in plasma of patients with heart failure. These data indicate that the posttranslational maturation processing of the B-type natriuretic peptide (BNP) precursor may not be efficient in heart failure. The aim of this chapter is to describe the biochemical pathways of proBNP108 maturation and to discuss the pathophysiological relevance of alteration of the posttranslational maturation mechanisms in heart failure. An impaired cardiac endocrine function was proposed to explain the altered electrolyte and fluid homeostasis occurring in chronic heart failure. Recent studies demonstrated that a great part of BNPs assayed by immunoassay methods in healthy subjects and in patients with cardiovascular disease is devoid of biological activity. These findings suggest that an alteration in posttranslational maturation of BNP precursor may promote the resistance to biological action of BNP in patients with heart failure at a prereceptor level. These studies also open a new and more complex scenario regarding the circulating BNPs. The active hormone (i.e., BNP1-32) may be produced even in vivo from the circulating precursor proBNP108 by plasma enzyme degradation, such as the soluble form of corin, possibly able to process the circulating intact precursor of natriuretic hormones. As a future perspective, the simultaneous measurement of the proBNP1-108 and the active peptide BNP1-32 with more specific methods could allow a more accurate estimation of both production/secretion of B-type-related peptides from cardiomyocytes and the true activity of the cardiac endocrine function.
 ...
PMID:Circulating forms of the b-type natriuretic peptide prohormone: pathophysiologic and clinical considerations. 2295 Mar 42


1 2 3 Next >>