Invited critical reviewCorin in clinical laboratory diagnostics
Highlights
► Corin is a transmembrane protease that processes natriuretic peptides. ► Corin is critical for maintaining normal blood pressure and cardiac function. ► Proteolytic shedding is an important mechanism in regulating corin activity. ► Soluble corin is detected in human blood and its levels are lower in patients with heart failure. ► Soluble corin may be used as a novel biomarker for heart failure.
Introduction
Proteolytic cleavage mediated by serine proteases plays an important role in many biological processes, including food digestion, inflammatory response, wound healing, hormone processing, blood coagulation, and fibrinolysis [1]. In the heart, for example, serine proteases such as tissue kallikrein, chymase and urokinase are involved in processing of many bioactive molecules, including bradykinin, angiotensin II, interleukin-1β, transforming growth factor-β, stem cell factor, and matrix metalloproteases [2]. These protease-mediated activities are critical in regulating blood pressure and cardiac function, and may contribute to pathological conditions such as hypertension, cardiac hypertrophy and heart failure (HF).
Most trypsin-like serine proteases are secreted proteins. More recently, a new class of type II transmembrane serine proteases (TTSPs) has been identified [3], [4], [5], which includes enteropeptidase [6], [7], [8], hepsin [9], [10], [11] and matriptases [12], [13], [14], [15]. All these proteases consist of an N-terminal cytoplasmic tail, a single-span transmembrane domain and an extracellular region with a C-terminal trypsin-like protease domain. Corin is a TTSP identified in the heart [16], [17], [18]. In this review, we describe the biology of corin and discuss recent findings of soluble corin in human blood and its potential use as a biomarker for the diagnosis of HF.
Section snippets
Corin protein and domain structure
Human corin is a protein of 1042 amino acids [18]. It contains an N-terminal cytoplasmic tail of 45 amino acids followed by a single-span transmembrane domain of 21 amino acids. The rest molecule is extracellular and contains several types of domains, including two frizzled-like domains, eight LDL receptor (LDLR)-like repeats, one scavenger receptor-like domain, and a C-terminal trypsin-like protease domain (Fig. 1). These distinct domains serve for specific functions [19], [20]. The
CORIN gene and expression
The human CORIN gene is located on the short arm of chromosome 4 at p12-13, a region adjacent to the centromere [18]. It has 22 exons and spans > 200 kb [27]. The intron–exon junctions correspond to boundaries of corin protein domains. For example, frizzled-like domains are encoded by two exons each whereas each LDLR repeat is encoded by one exon [27]. Such a genomic structure supports that the CORIN gene arose from exon duplication and rearrangement during evolution.
The mouse corin gene is
Corin in natriuretic peptide processing
Atrial and B-type or brain natriuretic peptides (ANP and BNP) are cardiac hormones that regulate body fluid balance and blood pressure [37], [38]. Upon binding to their receptor, these peptides stimulate intracellular cGMP production, thereby promoting natriuresis and diuresis in the kidney and muscle relaxation in the blood vessel. These peptide hormones are well conserved from primitive vertebrates to humans. In many migratory fish species such as salmon and eels, natriuretic peptides are
Corin shedding from the cell membrane
Ectodomain shedding is an important mechanism in regulating the function of a variety of membrane proteins, including adhesion molecules, enzymes, cytokines, growth factors, and receptors [63], [64]. Many TTSPs have soluble forms. In fact, enteropeptidase was first found in the intestinal juice by Ivan Pavlov, who won a Nobel Prize in 1904 for his discovery of digestive enzymes [5], [47]. What Pavlov found was likely a soluble form of enteropeptidase, which was shown to be released into the
Detection of soluble corin in human blood
By ELISA-based assays, soluble corin has been detected in human blood [29], [70], [71], [72], [73]. The levels in plasma and serum were similar [71], [73], indicating that soluble corin did not interact with activated platelets or clotting proteins. The reported values from five published studies are listed in Table 1. In addition to corin antigen, corin activity in human plasma was detected by pro-ANP or pro-BNP processing assays [29], [72]. To date, molecular forms of soluble corin in plasma
Plasma soluble corin in patients with HF
Corin is essential for maintaining normal blood pressure. In mice, corin deficiency causes spontaneous hypertension and cardiac hypertrophy [44], [75]. In African Americans, who are known for their high prevalence of cardiovascular disease, corin variants with impaired natriuretic peptide processing activity have been associated with hypertension [49], [76]. Patients with these variants developed severe cardiac hypertrophy and had poor clinical outcomes [77], [78]. These data suggest that corin
Perspectives
HF is a major disease. Effective managing this life-threatening disease depends on timely and accurate diagnosis. Currently, N-terminal pro-BNP and BNP are used as diagnostic markers to identify patients with HF [62], [86], [87]. The accuracy rates of these diagnostic tests are only ~ 75–85% in hospital emergency settings [88], [89], [90], [91]. Similar results also were reported in patients with chronic HF [92]. Therefore, more sensitive and accurate tests are needed to improve the diagnosis
Acknowledgments
This work was supported in part by grants from the National Natural Science Foundation of China (31070716), the Natural Science Foundation of the Jiangsu Higher Education Institutions (10KJB320017), and the Priority Academic Program Development of Jiangsu Higher Education Institutions of China, and grants from the Bakken Heart-Brain Institute, the Research Project Committee of the Cleveland Clinic, and the NIH (HL089298).
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Soluble Corin Predicts the Risk of Cardiovascular Disease: A 10-Year Follow-Up Study
2022, JACC: AsiaCitation Excerpt :Nevertheless, the causal effect of corin on stroke development still needs more evidence from trials. In the present study, the serum corin levels of each participant were measured using commercial enzyme-linked immunosorbent assays, which are also widely used in other studies.12,22-25 As an activator of the natriuretic peptides system, corin plays a critical role in maintaining blood pressure hemostasis through natriuresis, diuresis, and vasodilatation.2
Circulating soluble corin as a potential biomarker for cardiovascular diseases: A translational review
2018, Clinica Chimica ActaMolecular functions and specific roles of circRNAs in the cardiovascular system
2018, Non-coding RNA ResearchAssociation of rs2271037 and rs3749585 polymorphisms in CORIN with susceptibility to hypertension in a Chinese Han population: A case-control study
2018, GeneCitation Excerpt :The results implicated body weight control was important for individuals with CORIN rs2271037 (GT or GG) and/or CORIN rs3749585 (TT or CT) to protect them from hypertension. Previously, investigators have demonstrated that the levels and functions of corin may differ in disease states (Langenickel et al., 2004; Tran et al., 2004; Chan et al., 2005; Chen et al., 2010; Dong et al., 2010; Ibebuogu et al., 2011; Dong et al., 2012; Zaki et al., 2012; Fang et al., 2013; Peleg et al., 2013; Lee et al., 2014; Tarazon et al., 2014; Zhang et al., 2014; Pang et al., 2015; Peng et al., 2015). Posttranscriptional regulation by miRs in disease may yield these variations.
Fibrosis and Fibrotic Gene Expression in Pediatric and Adult Patients With Idiopathic Dilated Cardiomyopathy
2017, Journal of Cardiac FailureCitation Excerpt :Gal-3 is a β-galactoside–binding lectin that activates fibroblasts, which leads to increased deposition of collagen I.32–34 Corin is a cardiac serine protease that converts B-type natriuretic peptide (BNP) to its active form.35 Corin is decreased in adults with HF, which leads to impaired BNP processing.24,25 Interleukin-1 receptor–like 1 (ST2) is a member of the IL-1 receptor family and has 2 forms: ST2L, a transmembrane receptor; and sST2, which is a soluble decoy receptor.26