Abstract 1760: Corin Variant Associated with Hypertension and Cardiac Hypertrophy Exhibits Impaired Zymogen Activation and Natriuretic Peptide Processing Activity
Hypertension is the most common cardiovascular disease. Its prevalence in African-Americans is disproportionably high but the underlying cause is unclear. Corin is a cardiac protease that converts pro-atrial natriuretic peptide (ANP) to active ANP. Recently, two single nucleotide polymorphisms (SNPs) (T555I and Q568P) in the corin gene were identified in population genetic studies including the Dallas Heart, MESA, and Chicago Genetics of Hypertension Studies. The minor I555/P568 allele, which is more common in African-Americans, is associated with hypertension and cardiac hypertrophy. Here we examined if T555I and Q568P changes alter corin function. Plasmids encoding human corin variants were made by mutagenesis and expressed in human embryonic kidney (HEK) 293 cells. The corin expressing cells were incubated with human pro-ANP and pro-brain natriuretic peptide (BNP) at 37°C. The natriuretic peptide processing activity was assessed by analyzing pro-ANP/pro-BNP and their derivatives using immunoprecipitation and Western blotting. We found that mutant corin lacking frizzled-like domain 2, where T555I/Q568P changes occur, had 30 ± 5% (p < 0.01) pro-ANP processing activity compared to that of wild-type. Similarly, corin variant T555I/Q568P had a reduced activity (38 ± 7%, p < 0.01) compared to that of wild-type. The variant also exhibited a low activity (44 ± 15%, p < 0.05) in processing pro-BNP. We further identified the biochemical mechanism responsible for the impaired activity of the variant. In both HEK 293 cells and murine cardiomyocytic HL-1 cells, T555I/Q568P changes prevented the zymogen activation of the variant. By creating a new activation cleavage site, we were able to restore the activity of corin T555I/Q568P variant. Our results show that the corin gene SNPs associated with hypertension and cardiac hypertrophy impair corin zymogen activation and natriuretic peptide processing activity. Our data suggest that corin deficiency may be an important mechanism in hypertension and heart disease, especially among African-Americans.