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.

Atrial fibrillation (AF) is the most common form of sustained clinical arrhythmia. We previously mapped an AF locus to chromosome 5p13 in an AF family with sudden death in early childhood. Here we show that the specific AF gene underlying this linkage is NUP155, which encodes a member of the nucleoporins, the components of the nuclear pore complex (NPC). We have identified a homozygous mutation, R391H, in NUP155 that cosegregates with AF, affects nuclear localization of NUP155, and reduces nuclear envelope permeability. Homozygous NUP155(-/-) knockout mice die before E8.5, but heterozygous NUP155(+/-) mice show the AF phenotype. The R391H mutation and reduction of NUP155 are associated with inhibition of both export of Hsp70 mRNA and nuclear import of Hsp70 protein. These human and mouse studies indicate that loss of NUP155 function causes AF by altering mRNA and protein transport and link the NPC to cardiovascular disease.

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.)