Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0018799 (heart disease)
34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Corin cDNA encodes an unusual mosaic type II transmembrane serine protease, which possesses, in addition to a trypsin-like serine protease domain, two frizzled domains, eight low-density lipoprotein (LDL) receptor domains, a scavenger receptor domain, as well as an intracellular cytoplasmic domain. In in vitro experiments, recombinant human corin has recently been shown to activate pro-atrial natriuretic peptide (ANP), a cardiac hormone essential for the regulation of blood pressure. Here we report the first characterization of corin protein expression in heart tissue. We generated antibodies to two different peptides derived from unique regions of the corin polypeptide, which detected immunoreactive corin protein of approximately 125-135 kDa in lysates from human heart tissues. Immunostaining of sections of human heart showed corin expression was specifically localized to the cross striations of cardiac myocytes, with a pattern of expression consistent with an integral membrane localization. Corin was not detected in sections of skeletal or smooth muscle. Corin has been suggested to be a candidate gene for the rare congenital heart disease, total anomalous pulmonary venous return (TAPVR) as the corin gene colocalizes to the TAPVR locus on human chromosome 4. However examination of corin protein expression in TAPVR heart tissue did not show evidence of abnormal corin expression. The demonstrated corin protein expression by heart myocytes supports its proposed role as the pro-ANP convertase, and thus a potentially critical mediator of major cardiovascular diseases including hypertension and congestive heart failure.
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PMID:Localization of the mosaic transmembrane serine protease corin to heart myocytes. 1108 6

The Bowman-Birk inhibitor (BBI) is a small water-soluble protein present in soybean and almost all monocotyledonous and dicotyledonous seeds. The molecular size of BBI ranges from 1,513 Da to about 20,000 Da. BBI is to seeds what alpha(1)-antitrypsin is to humans. Soy-based food products rich in BBI include soybean grits, soymilk, oilcake, soybean isolate, and soybean protein concentrate. BBI is stable within the pH range encountered in most foods, can withstand boiling water temperature for 10 min, resistant to the pH range and proteolytic enzymes of the gastrointestinal tract, bioavailable, and not allergenic. BBI reduces the proteolytic activities of trypsin, chymotrypsin, elastase, cathepsin G, and chymase, serine protease-dependent matrix metalloproteinases, urokinase protein activator, mitogen activated protein kinase, and PI3 kinase, and upregulates connexin 43 (Cx43) expression. Several studies have demonstrated the efficacy of BBI against tumor cells in vitro, animal models, and human phase IIa clinical trials. FDA considers BBI as a drug. In 1999, FDA allowed a health claim on food labels stating that a daily diet containing 25 grams of soy protein, also low in saturated fat and cholesterol, may reduce the risk of heart disease [corrected] This review highlights the biochemical and functional food properties of the Bowman-Birk inhibitor.
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PMID:The biochemical and functional food properties of the bowman-birk inhibitor. 1827 67

Natriuretic peptides are important in regulating salt and body-fluid balance. In cells, these peptides are made as precursor forms that are converted to active forms by proteolyic processing. Corin is a transmembrane serine protease identified in the heart. Corin converts pro-atrial natriuretic peptide (pro-ANP) to active ANP in a sequence-specific manner. In mice, lack of corin prevents the conversion of pro-ANP to ANP and causes salt-sensitive hypertension. The hypertensive phenotype is exacerbated when the mice become pregnant. In humans, single nucleotide polymorphisms in the corin gene have been identified in African Americans with hypertension and cardiac hypertrophy. These data indicate that corin is important in maintaining normal blood pressure in vivo and that corin deficiency may contribute to hypertension and heart disease in patients.
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PMID:Corin: new insights into the natriuretic peptide system. 1871 1

The scabies mite (Sarcoptes scabiei) is a parasite responsible for major morbidity in disadvantaged communities and immuno-compromised patients worldwide. In addition to the physical discomfort caused by the disease, scabies infestations facilitate infection by Streptococcal species via skin lesions, resulting in a high prevalence of rheumatic fever/heart disease in affected communities. The scabies mite produces 33 proteins that are closely related to those in the dust mite group 3 allergen and belong to the S1-like protease family (chymotrypsin-like). However, all but one of these molecules contain mutations in the conserved active-site catalytic triad that are predicted to render them catalytically inactive. These molecules are thus termed scabies mite inactivated protease paralogues (SMIPPs). The precise function of SMIPPs is unclear; however, it has been suggested that these proteins might function by binding and protecting target substrates from cleavage by host immune proteases, thus preventing the host from mounting an effective immune challenge. In order to begin to understand the structural basis for SMIPP function, we solved the crystal structures of SMIPP-S-I1 and SMIPP-S-D1 at 1.85 A and 2.0 A resolution, respectively. Both structures adopt the characteristic serine protease fold, albeit with large structural variations over much of the molecule. In both structures, mutations in the catalytic triad together with occlusion of the S1 subsite by a conserved Tyr200 residue is predicted to block substrate ingress. Accordingly, we show that both proteases lack catalytic function. Attempts to restore function (via site-directed mutagenesis of catalytic residues as well as Tyr200) were unsuccessful. Taken together, these data suggest that SMIPPs have lost the ability to bind substrates in a classical "canonical" fashion, and instead have evolved alternative functions in the lifecycle of the scabies mite.
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PMID:Structural mechanisms of inactivation in scabies mite serine protease paralogues. 1942 18

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.
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PMID:Corin in clinical laboratory diagnostics. 2209 42

Dipeptidyl peptidase 4 (DPP4, DPPIV, CD26, EC 3.4.14.5) was discovered more than four decades ago as a serine protease that cleaves off N-terminal dipeptides from peptide substrates. The development of potent DPP4 inhibitors during the past two decades has led to the identification of DPP4 as a target in the treatment of type 2 diabetes. The favorable effect of DPP4 inhibitors is based on prevention of the in vivo inactivation of the incretin hormone, glucagon-like peptide-1 (GLP-1) by DPP4. Apart from GLP-1, a number of other biologically active peptides are truncated by DPP4. For these peptides, the physiological relevance of their truncation has yet to be fully elucidated. Within the last 10years, DPP4 inhibitors have been employed in several animal models of lung and heart disease, in which injury was induced by an ischemic insult followed by subsequent reperfusion. In this review, we present a state-of-the-art of the ischemia/reperfusion injury (IRI)-related pharmacological actions of DPP4 substrates, including GLP-1, stromal cell-derived factor-1 alpha and vasoactive intestinal peptide. Furthermore, we discuss the large body of experimental work that now provides compelling evidence for the advantageous impact of DPP4 targeting in IRI. However, possible risks as well as underlying mechanisms are yet to be elucidated before translating these promising treatment strategies into clinical practice.
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PMID:Dipeptidyl peptidase 4 as a therapeutic target in ischemia/reperfusion injury. 2285 May 30

Corin is a cardiac transmembrane serine protease that regulates blood pressure by activating natriuretic peptides. Corin variants have been associated with African Americans with hypertension and heart disease. Here, we report a new mutation in exon 12 of the CORIN gene identified in a family of patients with hypertension. The mutation resulted in R539C substitution in the Fz2 (Frizzled-2) domain of the corin propeptide region. We expressed and characterized the corin R539C mutant in HEK293 cells. As determined by Western blot analysis, the R539C mutation did not alter corin expression in transfected cells but impaired corin zymogen activation. In a pro-atrial natriuretic peptide processing assay, the corin mutant had reduced activity and exhibited a dominant-negative effect on wild-type corin. In addition, the R539C mutation altered corin ectodomain shedding, producing an alternative ~75-kDa fragment that was biologically inactive. Using protease inhibitors and the catalytically inactive corin mutant S985A, we showed that the ~75-kDa fragment was generated by corin autocleavage. We constructed a series of mutants by replacing single or double Arg residues in the corin propeptide and identified Arg-530 in the Fz2 domain as the alternative autocleavage site. Our results show that the corin mutation R539C identified in hypertensive patients impairs corin zymogen activation and causes an alternative autocleavage that reduces corin activity. These data support that human CORIN gene mutations causing impaired corin activity may be an underlying mechanism in hypertension.
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PMID:Corin mutation R539C from hypertensive patients impairs zymogen activation and generates an inactive alternative ectodomain fragment. 2337 61

Corin is a serine protease originally isolated from the heart. Functional studies show that corin is the long-sought enzyme responsible for activating cardiac natriuretic peptides. In mice, lack of corin prevents natriuretic peptide processing, causing salt-sensitive hypertension. In humans, corin variants and mutations that reduce corin activity have been identified in patients with hypertension and heart failure. Decreased plasma levels of corin antigen and activity have been reported in patients with heart failure and coronary artery disease. Low levels of urinary corin also have been found in patients with chronic kidney disease. Most recent studies show that corin also acts in the uterus to promote spiral artery remodeling and prevent pregnancy-induced hypertension. Here, we review the role of corin in natriuretic peptide processing and cardiovascular diseases such as hypertension, heart disease, pre-eclampsia, and chronic kidney disease.
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PMID:Corin in natriuretic peptide processing and hypertension. 2440 48

The systemic inflammatory response is a challenge in the management of paediatric patients undergoing cardiac surgery. Although multi-factorial, a contribution by the lectin pathway of complement activation has been postulated. We therefore investigated the changes in serum levels of mannose binding lectin (MBL) and activities of MBL-MBL-associated serine protease (MASP)-1 and MBL-MASP-2 complexes immediately before and during surgery, throughout the first postoperative day and at discharge from the hospital. These changes were analysed in relation to postoperative complications. Blood samples were obtained from 185 children with congenital heart disease undergoing surgical correction with the use of cardiopulmonary bypass: preoperatively (MBL-1), 15 min after initiation of cardiopulmonary bypass (CPB) (MBL-E), 30 min (MBL-2), 4 h (MBL-3), 12 h (MBL-4) and 24 h (MBL-5) post-CPB and at discharge from hospital (MBL-K). Alterations in serum MBL levels were calculated as a ratio of its serum level at subsequent time-points (MBL-2, -3, -4, -5) to the preoperative (MBL-1) value. Decreases in MBL and MBL-MASP complexes were observed in all samples, correlating with a decrease in C4 and increase in C4a, confirming activation of the lectin pathway. Changes in MBL levels between children with an uncomplicated postoperative course and those suffering from infection or low cardiac output syndrome did not differ significantly, but significant differences were observed between the SIRS and non-SIRS groups. Paediatric cardiac surgery with the use of cardiopulmonary bypass activates the complement system via the lectin pathway and the latter contributes to the development of the post-bypass systemic inflammatory response.
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PMID:Activation of the lectin pathway of complement by cardiopulmonary bypass contributes to the development of systemic inflammatory response syndrome after paediatric cardiac surgery. 2670 90

Heterozygous familial hypercholesterolemia (HeFH) is a common (early estimates suggested a prevalence of 1 in 500 individuals, but recent studies have indicated that it may be higher) genetic disorder characterized by markedly elevated plasma concentrations of low-density lipoprotein cholesterol (LDL-C). HeFH is associated with an elevated risk of premature coronary heart disease, stroke, and peripheral vascular disease. Despite the availability of reliable diagnostic criteria (high LDL-C levels, family history or premature CHD and hypercholesterolemia, cerebral/peripheral vascular disease, and the presence of tendon xanthomata or presence of arcus cornealis before age of 45), HeFH is underdiagnosed and undertreated worldwide. Moreover, while there are effective treatments available to decrease LDL-C and prevent early-onset heart disease in individuals with HeFH, because of the high baseline levels of LDL-C, the achievement of target LDL-C levels remains a challenge. In recent years, a number of novel therapies to lower LDL-C levels in HeFH have been developed, including the monoclonal antibodies against serine protease proprotein convertase subtilisin/kexin type 9 (PCSK9), alirocumab and evolocumab, which have the potential to reduce LDL-C by an additional 50%-60% when prescribed in combination with standard lipid-lowering drugs. This review summarizes the challenges in clinical management of subjects with HeFH, with a focus on emerging treatments, and highlights the status of HeFH diagnosis and treatment in Italy.
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PMID:Old challenges and new opportunities in the clinical management of heterozygous familial hypercholesterolemia (HeFH): The promises of PCSK9 inhibitors. 2799 83


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