Effect of Corin Deficiency and Mutation on Cardiac Natriuretic Peptide Processing in the Intact Heart Under Cardiac Pressure-Overload Conditions

Abstract

Natriuretic peptides ProANP and Pro BNP are translated as biologically-inactive pro-hormones that require proteolytic cleavage into biologically active carboxyl-terminal fragments by the serine protease Corin. Corin gene mutations are associated with risk for hypertension and left-ventricular hypertrophy in Blacks. However, the relative importance of Corin and the Corin T555I/Q568P mutations to proBNP processing in the heart is lacking. We adapted the Langendorff ex vivo cardiac perfusion model to allow dynamic assessment of cardiac processing of cardiac-derived proBNP using immunoassays specific for the murine molecular forms of unprocessed BNP1-95 and the active, carboxyl-terminus fragment murine BNP45. We also developed an inducible, cardiomyocyte-restricted Corin knockout mouse and a Corin T623I/Q636P homozygous knockin mouse to study the importance of cardiac Corin and the human Corin T555I/Q568P mutations to cardiac processing of proBNP. Results. As compared to WT controls, cardiomyocyte-restricted Corin knockout mice demonstrated significantly decreased BNP processing, and reduced myocardial cGMP and PKG kinase activity. The Corin623I(636P) knockin mice also demonstrated less severe but significant impairment in proBNP processing and reduced cardiac cGMP and PKG activity consistent with reduced GC-A activity. Cardiomyocyte Corin is essential to adequate processing of cardiac-derived proBNP and the autocrine/paracrine NPS. The murine Corin 623I(636P) heterozygous knockin model demonstrates impaired processing and reduced NPS autocrine/paracrine signaling during acute cardiac distention suggesting that Blacks heterozygous for the Corin I555(P568) haplotype may have reduced cardiac protection form the influence of chronic hypertension.