Summary In pregnancy, trophoblast invasion and uterine spiral artery remodeling are important for lowering maternal vascular resistance and increasing uteroplacental blood flow. Impaired spiral artery remodeling has long been implicated in preeclampsia, a major complication of pregnancy, but the underlying mechanisms remain unclear1, 2. Corin is a cardiac protease that activates atrial natriuretic peptide (ANP), a cardiac hormone important in regulating blood pressure3. Unexpectedly, corin expression was detected in the pregnant uterus4. Here we identify a novel function of corin and ANP in promoting trophoblast invasion and spiral artery remodeling. We show that pregnant corin- or ANP-deficient mice developed high blood pressure and proteinuria, characteristics of preeclampsia. In these mice, trophoblast invasion and uterine spiral artery remodeling were markedly impaired. Consistently, we find that ANP potently stimulated human trophoblasts in invading Matrigels. In patients with preeclampsia, uterine corin mRNA and protein levels were significantly lower than that in normal pregnancies. Moreover, we have identified corin gene mutations in preeclamptic patients, which decreased corin activity in processing pro-ANP. These results indicate that corin and ANP are essential for physiological changes at the maternal-fetal interface, suggesting that defects in corin and ANP function may contribute to preeclampsia.

Background-Corin is a transmembrane protease that processes natriuretic peptides in the heart. Like many membrane proteins, corin is shed from the cell surface. Methods and Results-In this study, we obtained plasma samples from healthy controls and patients with heart failure (HF) and acute myocardial infarction. Soluble corin levels in plasma were measured by an ELISA method. In healthy adults (nϭ198), plasma corin levels were 690 pg/mL (SD, 260 pg/mL). The corin levels did not differ significantly among different age groups. In patients with HF (nϭ291), plasma corin levels were significantly lower compared with that of healthy controls (365 pg/mL [SD, 259]; PϽ0.001). The reduction in plasma corin levels seemed to correlate with the severity of HF. In patients of New York Heart Association classes II, III, and IV, plasma corin levels were 450 pg/mL (SD, 281 pg/mL; nϭ69), 377 pg/mL (SD, 270 pg/mL; nϭ132), and 282 pg/mL (SD, 194 pg/mL; nϭ90), respectively (PϽ0.001 class II vs class IV; PϽ0.05 class III vs class IV). In contrast, plasma corin levels in patients with acute myocardial infarction (nϭ73) were similar to that of healthy controls (678 pg/mL [SD, 285 pg/mL]; PϾ0.05). Conclusions-Soluble corin was detected in human plasma. Plasma corin levels were reduced significantly in patients with HF but not in those with acute myocardial infarction. Our results indicate that corin deficiency may contribute to the pathogenesis of HF and that plasma corin may be used as a biomarker in the diagnosis of HF. (Circ Heart Fail. 2010;3:207-211.)

Hypertension is the most common cardiovascular disease, afflicting >30% of adults1. The cause of hypertension in most individuals remains unknown2,3, suggesting that additional contributing factors have yet to be discovered. Corin is a serine protease that activates the natriuretic peptides, thereby regulating blood pressure4. It is synthesized as a zymogen that is activated by proteolytic cleavage. CORIN variants and mutations impairing corin activation have been identified in people with hypertension and pre-eclampsia5–9. To date, however, the identity of the protease that activates corin remains elusive. Here we show that proprotein convertase subtilisin/kexin-6 (PCSK6, also named PACE4; ref. 10) cleaves and activates corin. In cultured cells, we found that corin activation was inhibited by inhibitors of PCSK family proteases and by small interfering RNAs blocking PCSK6 expression. Conversely, PCSK6 overexpression enhanced corin activation. In addition, purified PCSK6 cleaved wild-type corin but not the R801A variant that lacks the conserved activation site. Pcsk6-knockout mice developed salt-sensitive hypertension, and corin activation and pro-atrial natriuretic peptide processing activity were undetectable in these mice. Moreover, we found that CORIN variants in individuals with hypertension and pre-eclampsia were defective in PCSK6-mediated activation. We also identified a PCSK6 mutation that impaired corin activation activity in a hypertensive patient. Our results indicate that PCSK6 is the long-sought corin activator and is important for sodium homeostasis and normal blood pressure.

Plasma level determination uncovers antigen absence in acquired thrombotic thrombocytopenic purpura and ethnic differences.

Mechanisms underlying the vein development remain largely unknown. Tie2 signaling mediates endothelial cell (EC) survival and vascular maturation and its activating mutations are linked to venous malformations. Here we show that vein formation are disrupted in mouse skin and mesentery when Tie2 signals are diminished by targeted deletion of Tek either ubiquitously or specifically in embryonic ECs. Postnatal Tie2 attenuation resulted in the degeneration of newly formed veins followed by the formation of haemangioma-like vascular tufts in retina and venous tortuosity. Mechanistically, Tie2 insufficiency compromised venous EC identity, as indicated by a significant decrease of COUP-TFII protein level, a key regulator in venogenesis. Consistently, angiopoietin-1 stimulation increased COUP-TFII in cultured ECs, while Tie2 knockdown or blockade of Tie2 downstream PI3K/Akt pathway reduced COUP-TFII which could be reverted by the proteasome inhibition. Together, our results imply that Tie2 is essential for venous specification and maintenance via Akt mediated stabilization of COUP-TFII.DOI: http://dx.doi.org/10.7554/eLife.21032.001

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.

Background: Corin is a membrane serine protease that activates natriuretic peptides in the heart. Results: The corin mutant R539C identified in hypertensive patients has impaired zymogen activation and altered ectodomain shedding. Conclusion: The mutation alters corin protein structure and reduces corin activity. Significance: Human CORIN gene mutations causing impaired corin activity may be an underlying mechanism in hypertension.

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