Targeting the Epigenome Reduces Keloid Fibroblast Cell Proliferation, Migration and Invasion.

Keloids are pathological fibroproliferative scars resulting from abnormal collagen deposition within and beyond the margins of the initial cutaneous insult. Keloids negatively impact quality of life functionally and cosmetically, with current treatment modalities unsatisfactory. Recent studies indicate that epigenetic dysregulation is central to the development and progression of keloids. Here we evaluate the functional significance of epigenetic targeting strategies in vitro using patient-derived keloid fibroblasts treated with small molecule inhibitors of HDACs, LSD1, CoREST and p300, as potential therapies for keloids. We find that both the dual-acting CoREST inhibitor, corin, and the HDAC inhibitor, entinostat, reduce fibroblast proliferation more than the LSD1 inhibitor, GSK-LSD1; additionally, corin was the most effective inhibitor of migration and invasion across keloid fibroblasts. RNA-seq analysis of keloid fibroblasts treated with corin demonstrates coordinate upregulation of many genes including key mediators of cell adhesion such as claudins. Corin also downregulates gene sets involved in cell cycle progression, including reduced expression of cyclins A1 and B2 compared to DMSO. These results highlight a significant role for epigenetic regulation of pathologic mediators of keloidal scarring and suggest that inhibitors of the epigenetic CoREST repressor complex may prove beneficial in the prevention and/or treatment of keloidal scarring in patients.

The endocrine basis of the cardio-renal axis: New perspectives regarding corin.

The central role of natriuretic peptides (NPs) in the complex cardio-renal integrated physiology and organ failure has been revealed over the last four decades. Atrial natriuretic peptide (ANP), the oldest representative of the NPs family, is produced through conversion of proANP to the mature peptide by corin, a trans-membrane protease localized to the cardiac myocyte membrane. Similarly, brain natriuretic peptide (BNP) is generated by furin, which cleaves proBNP to BNP in myocytes. Though the components of NPs system, their synthesis and target organs are well established, understanding their role in the interplay between the heart and the kidney is steadily evolving. In this context, Feldman et al. (New England Journal of Medicine, 389, 1685) recently described patients with hypertension, cardiomyopathy, atrial arrhythmia and left atrial fibrosis, associated with a homozygous loss-of-function variant of the gene encoding corin (Cor-/-). Notably, reduced baseline urinary electrolyte and creatinine excretion have been observed in one of the studied patients. This renal excretory functional impairment could be attributed to the lack of cardiac-derived ANP in these patients, as implied by Feldman et al. Yet, in this mini-review we suggest that this aberrant renal manifestation may principally stem from lack of local ANP production at renal tissue, as corin is normally expressed in proximal tubules, Henle's loop and collecting ducts, with locally produced ANP provoking Na+ and water exertion. Collectively, it seems that beside the classic well-established cardio-renal axis, the renal NPs system functions as local endocrine machinery in the regulation of sodium excretion.

Plasma Corin: A New Biochemical Marker for Polycystic Ovary Syndrome.

INTRODUCTION: Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder. Atrial natriuretic peptide (ANP) is a risk factor for PCOS. Corin protein has an essential role in ANP synthesis. This study aimed to evaluate corin as a sensitive biomarker for PCOS. MATERIALS AND METHODS: A case-control study was conducted with 70 PCOS patients and 70 healthy females. Plasma Corin levels were quantified using enzyme-linked immunosorbent assay. RESULTS: The median plasma corin levels in PCOS patients and controls were 1785 and 822.5 pg/mL, respectively. Plasma corin levels were significantly elevated in PCOS patients than in the controls (p < 0.001). The optimal cut-off value was set at 1186 pg/mL. The sensitivity and specificity of Corin were 100% and 97.1%, respectively. Plasma corin levels were surrogate predictors for infertility in women with PCOS. It had an odds ratio of 5.9 (95% confidence interval: 1.1-32.7) (p = 0.04). Plasma corin levels were more highly detected in patients with PCOS than in the controls. CONCLUSION: Plasma corin level has reasonable diagnostic interpretation for PCOS. Corin appears as a worthy distinct predictor of infertility in PCOS women. Therefore, Corin may be a substantial biomarker for PCOS.

Association between CORIN promoter methylation and hypertensive disorders of pregnancy - A nested case-control study.

INTRODUCTION: Corin protein and its coding gene variants have been associated with hypertensive disorders of pregnancy (HDP), but the underlying mechanisms are unclear. As a mediator linking fixed genome with the dynamic environment, DNA methylation at the CORIN gene may link corin with HDP but not has been studied. This study aimed to examine whether CORIN promoter methylation and HDP in Chinese pregnant women. METHODS: Based on a cohort of Chinese pregnant women, we designed a nested case-control study including 196 cases with HDP and 200 healthy controls. DNA methylation levels in the CORIN promoter were quantified by pyrosequencing using peripheral blood before 20 gestational weeks. The association between DNA methylation in CORIN promoter and HDP was systemically examined by single CpG association analysis, followed by gene-based analysis. Multiple testing was controlled by the false discovery rate (FDR) method. RESULTS: The single CpG association analysis found that, among the 5 CpG sites assayed, hypermethylation at one CpG site (Chr4:47839945) was significantly associated with HDP (OR = 1.94, raw P = 0.020), but the significance did not survive for multiple testing correction (FDR-P = 0.100). The gene-based association analysis found that DNA methylation of the 5 CpG sites was jointly associated with HDP (raw P = 0.003). In addition to HDP, CORIN promoter methylation was also significantly associated with dynamic blood pressure during pregnancy (raw P < 0.05). DISCUSSION: Hypermethylation in CORIN promoter at early pregnancy was associated with the risk of HDP during late pregnancy in Chinese women. However, further evidence is required to establish the causality between CORIN promoter methylation and HDP.

Corin protects against acute kidney injury in mice through anti-inflammatory effects.

Corin is a type II transmembrane serine protease mainly expressed in the heart. Recently, corin was detected in the kidney and was reported to be associated with multiple kidney diseases. To date, its effect on acute kidney injury (AKI) has not been clarified. Here, we found that corin was constitutively expressed in renal tubules, especially in proximal and distal tubular epithelial cells. The expression of corin was dramatically reduced in ischemia/reperfusion injury (IRI)-induced AKI mouse model and oxygen-glucose deprivation (OGD)-induced human proximal tubular epithelial (HK-2) cells injury model, suggesting a potential role of corin in AKI. Corin deficient mice exhibited aggravated renal injury in AKI, as indicated by higher elevation of serum creatinine (SCr) and blood urea nitrogen (BUN), more severe tubular damage, and increased cell death versus wild type mice, demonstrating a protective effect of corin on AKI. In vitro overexpression of corin didn't directly alleviate hypoxia-induced HK-2 cells death, revealing that the protective effect of corin against AKI is not due to direct protection of tubular epithelial cells but may be through indirect protection. Microarray analysis showed enhanced inflammatory chemokines signaling and leukocyte chemotaxis in corin-/- mice after AKI, identifying an important role of corin in halting leukocyte chemotaxis and inflammatory response. Consistently, corin-/- mice after AKI displayed increased tubulointerstitial neutrophils and macrophages infiltration, as well as higher inflammatory mediators in kidneys. Taken together, our study indicates that tubular corin exerts a protective effect against AKI through negative regulation of chemotaxis signaling and inflammation in the kidney.

Corin deficiency alleviates mucosal lesions in a mouse model of colitis induced by dextran sulfate sodium.

AIMS: High dietary salt consumption is a risk factor for inflammatory bowel disease (IBD). Corin is a protease that activates atrial natriuretic peptide (ANP), thereby regulating sodium homeostasis. Corin acts in multiple tissues, including the intestine. In mice, corin deficiency impairs intestinal sodium excretion. This study aims to examine if reduced intestinal sodium excretion alters the pathophysiology of IBD. MAIN METHODS: Wild-type (WT), Corin knockout (KO), and Corin kidney conditional KO (kcKO) mice were tested in a colitis model induced by dextran sulfide sodium (DSS). Effects of ANP on DSS-induced colitis were tested in WT and Corin KO mice. Body weight changes in the mice were monitored. Necropsy, histological analysis, and immunostaining studies were conducted to examine colon length and mucosal lesions. Fecal sodium levels were measured. RT-PCR was done to analyze proinflammatory genes in colon samples. KEY FINDINGS: DSS-treated Corin KO mice had an ameliorated colitis phenotype with less body weight loss, longer colon lengths, smaller mucosal lesions, lower disease scores, more preserved goblet cells, and suppressed proinflammatory genes in the colon. In longitudinal studies, the DSS-treated Corin KO mice had delayed onset of colon mucosal lesions. ANP administration lessened the colitis in WT, but not Corin KO, mice. Analyses of WT, Corin KO, and Corin kcKO mice indicated that fecal sodium excretion, controlled by intestinal corin, may regulate inflammatory responses in DSS-induced colitis in mice. SIGNIFICANCE: Our findings indicate a role of corin in intestinal pathophysiology, suggesting that reduced intestinal sodium level may offer protective benefits against IBD.

Association of Preablation Plasma Corin Levels With Atrial Fibrillation Recurrence After Catheter Ablation: A Prospective Observational Study.

BACKGROUND: We assessed the impact of pre- and postprocedural plasma corin levels on the recurrence of atrial fibrillation (AF) after catheter ablation (CA). METHODS AND RESULTS: This prospective, single-center, observational study included patients undergoing their first CA of AF. Corin was measured before and 1 day after CA. The primary end point was recurrent AF between 3 and 12 months after ablation. From April 2019 through May 2021, we analyzed 616 patients with AF (59.09% men) with a mean age of 62.86±9.42 years. Overall, 153 patients (24.84%) experienced recurrent AF. In the recurrence group, the pre- and postprocedure corin concentrations were 539.14 (329.24-702.08) and 607.37 (364.50-753.80) pg/mL, respectively, which were significantly higher than the nonrecurrence group's respective concentrations of 369.05 (186.36-489.28) and 489.12 (315.66-629.05) pg/mL (both P<0.0001). A multivariate Cox regression analysis with confounders found that elevated preablation corin levels were significantly associated with an increased risk of AF recurrence after CA. Receiver operating characteristic curve analysis identified that a preablation corin threshold of >494.85 pg/mL predicted AF recurrence at 1 year. An increase of 1 SD in corin concentrations before CA (264.94 pg/mL) increased the risk of recurrent AF by 54.3% after adjusting for confounding variables (hazard ratio, 1.465 [95% CI, 1.282-1.655]; P<0.0001). CONCLUSIONS: Plasma corin levels at baseline is a valuable predictor of AF recurrence after CA, independent of established conventional risk factors. Risk stratification before ablation for AF may be useful in selecting treatment regimens for patients.

Golgi α-mannosidases regulate cell surface N-glycan type and ectodomain shedding of the transmembrane protease corin.

Corin is a transmembrane protease that activates natriuretic peptides on the cell membrane. Reduced cell surface targeting or increased ectodomain shedding disrupts cell membrane homeostasis of corin, thereby impairing its cell surface expression and enzyme activity. N-glycans are essential in corin ectodomain shedding. Lack of N-glycans promotes corin ectodomain shedding in the juxtamembrane and frizzled-1 domains. The nascent N-glycans, transferred onto the polypeptide of corin, undergo multistep N-glycan processing in the endoplasmic reticulum and Golgi. It remains unclear how trimming by Golgi α-mannosidases, the critical N-glycan processing steps in N-glycan maturation, may regulate corin biosynthesis. In this study, we examined the effects of kifunensine and swainsonine, the inhibitors for α-mannosidases I and II, on corin expression and function. Western analysis of corin proteins in cell lysates and conditioned media from the inhibitor-treated corin-stable HEK293 cells and AC16 cells showed that both α-mannosidases I and II were required to maintain complex N-glycans on cell surface corin and protect corin from ectodomain shedding in the juxtamembrane and frizzled-1 domains. Cell viability analysis revealed that inhibition of α-mannosidase I or II sensitized cardiomyocytes to hydrogen peroxide-induced injury via regulating corin. Moreover, either one of the two coding genes was sufficient to perform Golgi α-mannosidase I trimming of N-glycans on corin. Similarly, this sufficiency was observed in Golgi α-mannosidase II-coding genes. Inhibition of ectodomain shedding restored corin zymogen activation from kifunensine- or swainsonine-induced reduction. Together, our results show the important roles of Golgi α-mannosidases in maintaining cell membrane homeostasis and biological activities of corin.

Corin deficiency impairs cardiac function in mouse models of heart failure.

Introduction: Corin is a protease in the natriuretic peptide system. Deleterious CORIN variants are associated with hypertension and heart disease. It remains unclear if and to what extent corin deficiency may contribute to heart failure (HF). Methods: Corin knockout (KO) mice were used as a model. Cardiac function was assessed by echocardiography and tissue analysis in Corin KO mice at different ages or subjected to transverse aortic constriction (TAC), which increased pressure overload. Heart and lung tissues were analyzed for cardiac hypertrophy and lung edema using wheat germ agglutinin, Sirius red, Masson's trichrome, and Prussian blue staining. Recombinant corin was tested for its effect on cardiac function in the TAC-operated Corin KO mice. Selected gene expression in the heart was examined by RT-PCR. ELISA was used to analyze factors in plasma. Results: Corin KO mice had progressive cardiac dysfunction with cardiac hypertrophy and fibrosis after 9 months of age, likely due to chronic hypertension. When Corin KO mice were subjected to TAC at 10-12 weeks of age, cardiac function decreased more rapidly than in similarly treated wild-type mice. When the TAC-operated Corin KO mice were treated with recombinant corin protein, cardiac dysfunction, hypertrophy, and fibrosis were ameliorated. The corin treatment also decreased the gene expression associated with cardiac hypertrophy and fibrosis, increased plasma cGMP levels, lowered plasma levels of N-terminal pro-atrial natriuretic peptide, angiotensin II, and aldosterone, and lessened lung edema in the Corin KO mice subjected to TAC. Conclusion: Corin deficiency impairs cardiac function and exacerbates HF development in mice. Corin protein may be used to reduce cardiac hypertrophy and fibrosis, suppress the renin-angiotensin-aldosterone system, and improve cardiac function in HF.

Natriuretic Peptide Signaling in Uterine Biology and Preeclampsia.

Endometrial decidualization is a uterine process essential for spiral artery remodeling, embryo implantation, and trophoblast invasion. Defects in endometrial decidualization and spiral artery remodeling are important contributing factors in preeclampsia, a major disorder in pregnancy. Atrial natriuretic peptide (ANP) is a cardiac hormone that regulates blood volume and pressure. ANP is also generated in non-cardiac tissues, such as the uterus and placenta. In recent human genome-wide association studies, multiple loci with genes involved in natriuretic peptide signaling are associated with gestational hypertension and preeclampsia. In cellular experiments and mouse models, uterine ANP has been shown to stimulate endometrial decidualization, increase TNF-related apoptosis-inducing ligand expression and secretion, and enhance apoptosis in arterial smooth muscle cells and endothelial cells. In placental trophoblasts, ANP stimulates adenosine 5'-monophosphate-activated protein kinase and the mammalian target of rapamycin complex 1 signaling, leading to autophagy inhibition and protein kinase N3 upregulation, thereby increasing trophoblast invasiveness. ANP deficiency impairs endometrial decidualization and spiral artery remodeling, causing a preeclampsia-like phenotype in mice. These findings indicate the importance of natriuretic peptide signaling in pregnancy. This review discusses the role of ANP in uterine biology and potential implications of impaired ANP signaling in preeclampsia.

Corin Deficiency Diminishes Intestinal Sodium Excretion in Mice.

Sodium excretion, a critical process in sodium homeostasis, occurs in many tissues, including the kidney and intestine. Unlike in the kidney, the hormonal regulation of intestinal sodium excretion remains unclear. Atrial natriuretic peptide (ANP) is a crucial hormone in renal natriuresis. Corin is a protease critical for ANP activation. Corin and ANP are expressed mainly in the heart. In this study, we investigated corin, ANP, and natriuretic peptide receptor A (Npra) expression in mouse intestines. Corin and ANP expression was co-localized in enteroendocrine cells, whereas Npra expression was on the luminal epithelial cells. In Corin knockout (KO) mice, fecal Na+ and Cl- excretion decreased compared with that in wild-type (WT) mice. Such a decrease was not found in conditional Corin KO mice lacking cardiac corin selectively. In kidney conditional Corin KO mice lacking renal corin, fecal Na+ and Cl- excretion increased, compared to that in WT mice. When WT, Corin KO, and the kidney conditional KO mice were treated with aldosterone, the differences in fecal Na+ and Cl- levels disappeared. These results suggest that intestinal corin may promote fecal sodium excretion in a paracrine mechanism independent of the cardiac corin function. The increased fecal sodium excretion in the kidney conditional Corin KO mice likely reflected an intestinal compensatory response to renal corin deficiency. Our results also suggest that intestinal corin activity may antagonize aldosterone action in the promotion of fecal sodium excretion. These findings help us understand the hormonal mechanism controlling sodium excretion the intestinal tract.

Type II Transmembrane Serine Proteases as Modulators in Adipose Tissue Phenotype and Function.

Adipose tissue is a crucial organ in energy metabolism and thermoregulation. Adipose tissue phenotype is controlled by various signaling mechanisms under pathophysiological conditions. Type II transmembrane serine proteases (TTSPs) are a group of trypsin-like enzymes anchoring on the cell surface. These proteases act in diverse tissues to regulate physiological processes, such as food digestion, salt-water balance, iron metabolism, epithelial integrity, and auditory nerve development. More recently, several members of the TTSP family, namely, hepsin, matriptase-2, and corin, have been shown to play a role in regulating lipid metabolism, adipose tissue phenotype, and thermogenesis, via direct growth factor activation or indirect hormonal mechanisms. In mice, hepsin deficiency increases adipose browning and protects from high-fat diet-induced hyperglycemia, hyperlipidemia, and obesity. Similarly, matriptase-2 deficiency increases fat lipolysis and reduces obesity and hepatic steatosis in high-fat diet-fed mice. In contrast, corin deficiency increases white adipose weights and cell sizes, suppresses adipocyte browning and thermogenic responses, and causes cold intolerance in mice. These findings highlight an important role of TTSPs in modifying cellular phenotype and function in adipose tissue. In this review, we provide a brief description about TTSPs and discuss recent findings regarding the role of hepsin, matriptase-2, and corin in regulating adipose tissue phenotype, energy metabolism, and thermogenic responses.

Association between CORIN promoter methylation and stroke: Results from two independent samples of Chinese adults.

Objective: As the physical activator of natriuretic peptides, corin has been associated with stroke, but the underlying mechanism is not very clear. Here, we examined whether the CORIN promoter's methylation, an epigenetic DNA modification, was associated with the risk of stroke in two independent samples. Methods: A total of 1771 participants including 853 stroke cases and 918 healthy controls were included as a discovery sample and 2,498 community members with 10 years of follow-up were included as a replication sample. DNA methylation of the CORIN promoter was quantified by target bisulfite sequencing in both samples. We first examined the single CpG association, followed by a gene-based analysis of the joint association between multiple CpG methylation and stroke, adjusting for conventional risk factors. Results: The single CpG association analysis found that hypermethylation at all of the 9 CpG sites assayed was significantly associated with lower odds of prevalent stroke in the discovery sample (all p < 0.05), and three of them located at Chr4:47840038 (HR = 0.74, p = 0.015), Chr4:47839941 (HR = 0.80, p = 0.047), and Chr4:47839933 (HR = 0.82, p = 0.050) were also significantly associated with incident stroke in the replication sample. The gene-based association analysis found that DNA methylation of the 9 CpG sites at the CORIN promoter was jointly associated with stroke in both samples (all p < 0.05). Conclusion: DNA methylation levels of the CORIN gene promoter were lower in stroke patients and predicted a higher risk of incident stroke in Chinese adults. The underlying causality warranted further investigation.

Investigating the Effects of Atrial Natriuretic Peptide on the Maternal Endothelium to Determine Potential Implications for Preeclampsia.

Preeclampsia is associated with an increased lifelong risk of cardiovascular disease (CVD). It is not clear whether this is induced by persistent systemic organ and vascular damage following preeclampsia or due to a predisposition to both conditions that share cardiovascular pathophysiology. Common to both CVD and preeclampsia is the dysregulation of corin and its proteolytic product, atrial natriuretic peptide (ANP). ANP, a hypotensive hormone converted from pro-ANP by corin, is involved in blood pressure homeostasis. While corin is predominantly a cardiac enzyme, both corin and pro-ANP are significantly upregulated in the gravid uterus and dysregulated in preeclampsia. Relatively little is known about ANP function in the endothelium during a pregnancy complicated by preeclampsia. Here, we investigated the effect of ANP on endothelial cell proliferation and migration, markers of endothelial dysfunction, and receptor expression in omental arteries exposed to circulating preeclamptic toxins. ANP receptor expression is significantly upregulated in preeclamptic vasculature but not because of exposure to preeclampsia toxins tumour necrosis factor α or soluble fms-like tyrosine kinase-1. The supplementation of endothelial cells with ANP did not promote proliferation or migration, nor did ANP improve markers of endothelial dysfunction. The role of ANP in preeclampsia is unlikely to be via endothelial pathways.

Associations of genetic polymorphisms in Corin with blood pressure responses to salt and potassium intake / 西安交通大学学报(医学版)

【Objective】 Corin, a transmembrane serine protease that can cleave atrial natriuretic peptide precursor (pro-ANP) into atrial natriuretic peptide with smaller bioactive molecules, participates in the pathophysiological process of hypertension and cardiac hypertrophy. The purpose of this study was to explore the relationship of Corin gene variation with blood pressure responses to sodium and potassium dietary interventions. 【Methods】 In 2004, we recruited 514 participants from 124 families in 7 villages of Baoji, Shaanxi Province, China. All the subjects received a 3-day normal diet, a 7-day low-salt diet, a 7-day high-salt diet, and finally a 7-day high-salt and potassium supplementation. Fifteen single nucleotide polymorphisms (SNPs) of Corin gene were selected for final analysis. 【Results】 SNPs rs12509275 were significantly associated with diastolic blood pressure (DBP) response to low-salt diet, while rs3749584 was associated with pulse pressure (PP) response to low-salt diet.SNP rs3749584 and rs10517195 were significantly associated with PP response to high-salt diet. In addition,rs17654278 were significantly associated with systolic blood pressure (SBP) response to high-salt and potassium supplementation, rs2271037 was significantly correlated with DBP responses to high-salt and potassium supplementation, and rs4695253, rs12509275, rs2351783, rs36090894 were significantly associated with PP response to high-salt and potassium supplementation. 【Conclusion】 Corin gene polymorphisms were associated with blood pressure response to sodium and potassium, suggesting that Corin gene may be involved in pathophysiological process of salt sensitivity and potassium sensitivity.

Corin is regulated by circ-0012397/miR-200a-3p and inhibits the oxygen-glucose deprivation-induced apoptosis of SHSY5Y neuroblastoma cells.

Background: As a type II transmembrane serine protease, corin plays a role in several important physiological and pathological processes. We conducted a bioinformatics analysis to explore the roles of both corin and circ-0012397/miR-200a-3p in ischemic stroke. Methods: We established an in vitro model using oxygen-glucose deprivation (OGD)-induced SHSY5Y cells. The proliferation and apoptosis of SHSY5Y cells was determined using Cell Counting Kit-8 (CCK-8) and flow cytometry/Hoechst 33258 staining, respectively. The RNA and protein level was tested using Real Time Quantitative Polymerase Chain Reaction (RT-qPCR) and western blot, respectively. The regulatory relationship of corin and circ-0012397/miR-200a-3p were detected by dual-luciferase reporter assays. Results: We found that OGD downregulated the expression of corin in a time-dependent manner; this change was inversely proportional to the rate of apoptosis of the SHSY5Y cells. Further, high expression levels of corin enhanced the proliferation of SHSY5Y cells and inhibited the apoptosis of SHSY5Y cells by downregulating the expression of cleaved caspase-3, B-cell lymphoma 2 (BCL-2)-associated death promoter, extracellular-regulated protein kinase (ERK), and protein 38 (p38), and upregulated the expression of Bcl-2. Further, the dual-luciferase reporter assays and RT-qPCR showed that corin expression was regulated by circ-0012397/miR-200a-3p. Corin expression was affected by changes in circ-0012397 and miR-200a-3p expression, which were overexpressed or inhibited. Further, corin exerted different regulatory effects on apoptosis signaling-related proteins, including AD Bcl-2, cleaved caspase-3, ERK, and p38, under different expression levels of circ-0012397 and miR-200a-3p. Conclusions: Corin promotes the cell proliferation and inhibits OGD-induced apoptosis of SHSY5Y cells, and that its expression is regulated by circ-0012397/miR-200a-3p. Thus, corin may be a potential target for ischemic stroke patients.

A Prediction Model for Rapid Identification of Ischemic Stroke: Application of Serum Soluble Corin.

Objective: Rapid identification is critical for ischemic stroke due to the very narrow therapeutic time window. The objective of this study was to construct a diagnostic model for the rapid identification of ischemic stroke. Methods: A mixture population constituted of patients with ischemic stroke (n = 481), patients with hemorrhagic stroke (n = 116), and healthy individuals from communities (n = 2498) were randomly resampled into training (n = 1547, mean age: 55 years, 44% males) and testing (n = 1548, mean age: 54 years, 43% males) samples. Serum corin was assayed using commercial ELISA kits. Potential risk factors including age, sex, education level, cigarette smoking, alcohol consumption, obesity, blood pressure, lipids, glucose, and medical history were obtained as candidate predictors. The diagnostic model of ischemic stroke was developed using a backward stepwise logistic regression model in the training sample and validated in the testing sample. Results: The final diagnostic model included age, sex, cigarette smoking, family history of stroke, history of hypertension, systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, fasting glucose, and serum corin. The diagnostic model exhibited good discrimination in both training (AUC: 0.910, 95% CI: 0.884-0.936) and testing (AUC: 0.907, 95% CI: 0.881-0.934) samples. Calibration curves showed good concordance between the observed and predicted probability of ischemic stroke in both samples (all P>0.05). Conclusion: We developed a simple diagnostic model with routinely available variables to assist rapid identification of ischemic stroke. The effectiveness and efficiency of this model warranted further investigation.

Proprotein Convertase Subtilisin/Kexin 6 in Cardiovascular Biology and Disease.

Proprotein convertase subtilisin/kexin 6 (PCSK6) is a secreted serine protease expressed in most major organs, where it cleaves a wide range of growth factors, signaling molecules, peptide hormones, proteolytic enzymes, and adhesion proteins. Studies in Pcsk6-deficient mice have demonstrated the importance of Pcsk6 in embryonic development, body axis specification, ovarian function, and extracellular matrix remodeling in articular cartilage. In the cardiovascular system, PCSK6 acts as a key modulator in heart formation, lipoprotein metabolism, body fluid homeostasis, cardiac repair, and vascular remodeling. To date, dysregulated PCSK6 expression or function has been implicated in major cardiovascular diseases, including atrial septal defects, hypertension, atherosclerosis, myocardial infarction, and cardiac aging. In this review, we describe biochemical characteristics and posttranslational modifications of PCSK6. Moreover, we discuss the role of PCSK6 and related molecular mechanisms in cardiovascular biology and disease.