Protease corin expression and activity in failing hearts

Chen, Shenghan; Sen, Subha; Young, D. R.; Wang, Wei; Moravec, Christine S.; Wu, Qingyu

doi:10.1152/ajpheart.00399.2010

Cited by 68 publications

(68 citation statements)

References 43 publications

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“…Interestingly, we and others found that plasma corin levels were lower in patients with severe HF compared with that in normal individuals or patients with less severe HF (18,21,22). We also found that cardiac corin protein expression, but not its activity, was increased in mouse and human failing hearts, indicating that corin activation is a ratelimiting step in HF (40). As shown in this study, corin shedding and autocleavage were closely related to its activation.…”

Section: Discussionsupporting

confidence: 74%

Ectodomain Shedding and Autocleavage of the Cardiac Membrane Protease Corin

Jiang

Wang

et al. 2011

Journal of Biological Chemistry

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Corin is a cardiac membrane protease that activates natriuretic peptides. It is unknown how corin function is regulated. Recently, soluble corin was detected in human plasma, suggesting that corin may be shed from cardiomyocytes. Here we examined soluble corin production and activity and determined the proteolytic enzymes responsible for corin cleavage. We expressed human corin in HEK 293 cells and detected three soluble fragments of ϳ180, ϳ160, and ϳ100 kDa, respectively, in the cultured medium by Western blot analysis. All three fragments were derived from activated corin molecules. Similar results were obtained in HL-1 cardiomyocytes. Using protease inhibitors, ionomycin and phorbol myristate acetate stimulation, small interfering RNA knockdown, and site-directed mutagenesis, we found that ADAM10 was primarily responsible for shedding corin in its juxtamembrane region to release the ϳ180-kDa fragment, corresponding to the near-entire extracellular region. In contrast, the ϳ160-and ϳ100-kDa fragments were from corin autocleavage at Arg-164 in frizzled 1 domain and Arg-427 in LDL receptor 5 domain, respectively. In functional studies, the ϳ180-kDa fragment activated atrial natriuretic peptide, whereas the ϳ160-and ϳ100-kDa fragments did not. Our data indicate that ADAM-mediated shedding and corin autocleavage are important mechanisms regulating corin function and preventing excessive, potentially hazardous, proteolytic activities in the heart. Natriuretic peptides act as a cardiac endocrine mechanism to regulate blood volume and pressure (1, 2). Corin is a serine protease that activates atrial natriuretic peptides (ANP) 2 and B-type natriuretic peptides in the heart (3, 4). The physiological importance of corin function has been shown in mouse models, in which disruption of the corin gene causes hypertension and cardiac hypertrophy (5, 6). In humans, population studies have identified polymorphisms (T555I/Q568P) in the corin gene in African Americans who had high blood pressure and cardiac hypertrophy (7-9). The polymorphisms were shown to alter corin protein structure and impair its biological activity in functional studies (10). In patients with heart failure (HF), the corin variants were associated with poor natriuretic peptide processing and worse clinical outcomes (11).Corin belongs to the type II transmembrane serine protease family, a subclass of trypsin-like enzymes defined by an N-terminal transmembrane domain and a C-terminal protease domain (12, 13). The transmembrane domain anchors the proteases on the cell surface, localizing the biological activities at specific sites. Under physiological and/or pathological conditions, type II transmembrane serine proteases can be shed from the cell surface. Soluble forms of enteropeptidase, hepsin and matriptases, for example, have been reported (14 -17). Recently, soluble corin was detected in human blood, indicating that corin is shed from the heart (18 -20). Interestingly, plasma corin levels were lower in patients with severe HF compared with those of normal...

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Section: Discussionsupporting

confidence: 74%

Ectodomain Shedding and Autocleavage of the Cardiac Membrane Protease Corin

Jiang

Wang

et al. 2011

Journal of Biological Chemistry

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“…The fact that corin has been placed center-stage in the study of the progression of heart diseases highlights the importance of exploring the association between corin expression and RIHD severity and/or phenotype in cancer patients receiving radiotherapy (21). The two most intensively studied substrates of corin, ANP and BNP, are closely linked to compensatory mechanisms in failing hearts (11,21).…”

Section: Discussionmentioning

confidence: 99%

Involvement of corin downregulation in ionizing radiation-induced senescence of myocardial cells

Kim

Lee

Jung

et al. 2014

International Journal of Molecular Medicine

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Abstract. Radiation-induced heart disease (RIHD) is becoming an increasing concern for patients and clinicians alike due to the use of radiotherapy for the treatment of breast cancer, Hodgkin's lymphoma, pediatric cancer and tumors of the thorax. However, the mechanisms underlying this phenomenon remain largely unknown. As the senescent cell fraction following irradiation is known to increase, in the present study, we investigated whether ionizing radiation (IR) causes the onset of heart disease by inducing cellular senescence in cardiomyocytes. In the present study, we evaluated the effects of IR on HL-1 and H9C2 cells, cells predominantly used in in vitro myocardial cell models. We found that the exposure of the HL-1 and H9C2 cells to IR induced reactive oxygen species (ROS)-mediated cellular senescence, as shown by staining of senescence-associated β-galactosidase (SA-β-gal). The levels of ROS in irradiated cells were determined using the fluorescent dye, 2' , 7'-dichlorodihydrofluorescein diacetate (DCF-DA). Notably, the expression of corin, a cardiac protease that is essential for the proteolytic cleavage of natriuretic peptides, was significantly decreased following the exposure of the cells to IR. Importantly, the knockdown of corin by RNA interference enhanced IR-induced senescence. On the contrary, the overexpression of natriuretic peptides reversed the IR-induced senescence. Taken together, our data suggest that defects in corin function and the inhibition of natriuretic peptides following exposure to IR may contribute to the development of RIHD through the acceleration of cellular senescence.

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“…Corin is a type II transmembrane serine protease that is highly expressed in cardiomyocytes (1)(2)(3)(4). The human corin gene is mapped to chromosome 4p12-13 (1) and encodes a polypeptide of 1,042 amino acids (5).…”

Section: Introductionmentioning

confidence: 99%

IL-1β increases urinary corin in patients with primary proteinuric kidney diseases and in 293 cells

et al. 2017

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Abstract. Corin is a serine protease that is important for the regulation of blood pressure and water balance. Corin was initially discovered in the heart, however, it has also been detected in kidney cells, though its function in the kidneys is unclear. To further investigate the function of corin in the kidney, the present study analyzed the levels of corin in urine and blood samples collected from normal individuals and patients with primary proteinuric diseases. The associations between the levels of corin, and the cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) were then assessed. The results demonstrated that corin was detectable in the urine and plasma following an enzyme-linked immunosorbent assay; the level of corin in the urine was associated with the level of urinary β 2 -microglobulin (P=0.01), which was indicative of renal tubular injury. When compared with normal individuals, the levels of urinary corin in proteinuric patients were markedly increased (P=0.02), and were also associated with IL-1β (P=0.03). This correlation between corin and IL-1β was confirmed in vitro using 293 cells. As the IL-1β concentrations increased (0, 0.1, 1, 10 ng/ml), an elevation in the level of corin was observed in the culture medium (P<0.01); however, the amount of corin was not markedly altered in the cell lysate (P>0.05). In addition, when TNF-α reached 10 ng/ml, the level of corin in the medium increased significantly when compared with the control group (0 ng/ml; P=0.02), however, no significant difference in corin levels was detected in the cell lysate. The results suggest that the cytokines IL-1β and TNF-α may increase urinary corin in patients with primary proteinuric kidney diseases. Cytokines may accelerate corin shedding from the cell membrane of renal tubule epithelial cells. These findings indicate that corin may be associated with kidney inflammation and injury.

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Protease corin expression and activity in failing hearts

Cited by 68 publications

References 43 publications

Ectodomain Shedding and Autocleavage of the Cardiac Membrane Protease Corin

Ectodomain Shedding and Autocleavage of the Cardiac Membrane Protease Corin

Involvement of corin downregulation in ionizing radiation-induced senescence of myocardial cells

IL-1β increases urinary corin in patients with primary proteinuric kidney diseases and in 293 cells

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