Atrial natriuretic peptide (ANP) is a cardiac hormone that regulates blood pressure. In cardiomyocytes, the hormone is synthesized as a precursor, proatrial natriuretic peptide (pro-ANP), which is proteolytically converted to active ANP. Corin is a cardiac transmembrane serine protease that has been shown to process pro-ANP in vitro, but its physiological importance had not been established. Here, we show that corin-deficient (Cor ؊/؊ ) mice develop normally during embryogenesis and survive to postnatal life. Cor ؊/؊ mice have elevated levels of pro-ANP but no detectable levels of ANP as compared with WT littermates. Infusion of an active recombinant soluble corin transiently restores pro-ANP conversion, resulting in the release of circulating biologically active ANP. Using radiotelemetry to assess blood pressure, we find that Cor ؊/؊ mice have spontaneous hypertension as compared with WT mice, and it is enhanced after dietary salt loading. Pregnant Cor ؊/؊ mice demonstrate late-gestation proteinuria and enhanced high blood pressure during pregnancy. In addition, Cor ؊/؊ mice exhibit cardiac hypertrophy resulting in a mild decline in cardiac function later in life. Thus, our data establish corin as the physiological pro-ANP convertase and indicate that corin deficiency may contribute to hypertensive heart disease.blood pressure ͉ cardiac hypertrophy ͉ preeclampsia ͉ serine protease A trial natriuretic peptide (ANP) is a peptide hormone synthesized in the heart as an inactive precursor, proatrial natriuretic peptide (pro-ANP), which is stored in the dense granules of cardiomyocytes. In response to volume expansion and pressure overload, pro-ANP is secreted from cardiomyocytes and proteolytically cleaved, converting it to the mature peptide, ANP. In target organs such as kidney and blood vessels, ANP stimulates production of intracellular cGMP in a receptordependent manner, leading to natriuresis, diuresis, and vasodilatation, thereby decreasing blood pressure through reduction of intravascular volume and systemic vascular resistance (for review, see ref. 1). Despite the importance of the ANP-mediated pathway in regulating blood pressure and body fluid homeostasis, the enzyme(s) responsible for pro-ANP conversion remained poorly defined.Corin is a type II transmembrane serine protease highly expressed in the heart (2-4). Cell-based studies have shown that recombinant human corin converts pro-ANP to active ANP in a sequence-specific manner (5, 6). More recently, purified recombinant human corin also has been shown to process pro-ANP (7), indicating that corin is likely the pro-ANP convertase. Because other proteases such as thrombin and kallikrein have also been reported to cleave pro-ANP in vitro (8,9), it remained to be demonstrated whether corin indeed is the physiological pro-ANP convertase.To define the biological role of corin, we generated corindeficient mice (Cor Ϫ/Ϫ ) by homologous recombination. Our results show that pro-ANP conversion was abolished in these mice. Cor Ϫ/Ϫ mice develop hypertension that is...
