Pregnancy-Associated Cardiac Hypertrophy in Corin-Deficient Mice: Observations in a Transgenic Model of Preeclampsia

Abstract

Background: Preeclampsia increases the risk of heart disease. Defects in the protease corin, including the variant T555I/Q568P found in approximately 12% of blacks, have been associated with preeclampsia and cardiac hypertrophy. The objective of this study was to investigate the role of corin and the T555I/Q568P variant in preeclampsia-associated cardiac alterations using genetically modified mouse models.

Methods: Virgin wild-type (WT) and corin knockout mice with or without a cardiac WT corin or T555I/Q568P variant transgene were mated at 3 or 6 months of age. Age- and genotype-matched virgin mice were used as controls. Cardiac morphology and function were assessed at gestational day 18.5 or 28 days postpartum by histologic and echocardiographic analyses.

Results: Pregnant corin knockout mice at gestational day 18.5 developed cardiac hypertrophy. Such a pregnancy-associated phenotype was not found in WT or corin knockout mice with a cardiac WT corin transgene. Pregnant corin knockout mice with a cardiac T555I/Q568P variant transgene developed cardiac hypertrophy similar to that in pregnant corin knockout mice. The cardiac hypertrophy persisted postpartum in corin knockout mice and was worse if the mice were mated at 6 instead of 3 months of age. There was no hypertrophy-associated decrease in cardiac function in pregnant corin knockout mice.

Conclusions: In mice, corin deficiency causes cardiac hypertrophy during pregnancy. Replacement of cardiac WT corin, but not the T555I/Q568P variant found in blacks, rescues this phenotype, indicating a local antihypertrophic function of corin in the heart. Corin deficiency may represent an underlying mechanism in preeclampsia-associated cardiomyopathies.

Figure 1.

Cardiac hypertrophy in Corin KO mice mated at 3 months of age. Hearts were collected at GD18.5 or 28 days postpartum from WT and Corin KO mice and compared to age-matched corresponding virgin controls. (A) Heart weight normalized to tibia length in WT and Corin KO mice. (B) Representative images of H&E-stained heart sections at 20× and 400× magnifications; bars: 500 μm (left column) and 20 μm (right column). (C) Quantitative analysis of cardiomyocyte diameters in WT and Corin KO mice; Data are mean ± SEM from 100 individual cardiomyocytes in >3 randomly selected LV sections from each animal; n=8–11 per group, ns: not statistically significant.

Figure 2.

Cardiac hypertrophy in Corin KO mice mated at 6 months of age. Hearts were collected at GD18.5 or 28 days postpartum from WT and Corin KO mice and compared to age-matched corresponding virgin controls. (A) Heart weight normalized to tibia length in WT and Corin KO mice. (B) Representative images of H&E-stained heart sections at 20× and 400× magnifications, bars: 500 μm (left column) and 20 μm (right column). (C) Quantitative analysis of cardiomyocyte diameters in WT and Corin KO mice; Data are mean ± SEM from 100 individual cardiomyocytes in >3 randomly selected LV sections from each animal; n=7–8 per group, ns: not statistically significant.

Figure 3.

LV systolic function in pregnant WT and Corin KO mice. LV systolic echocardiography measurements in WT and Corin KO mice mated at 6 months of age. Echos were performed before mating (baseline) and at GD10.5, GD18.5, and 28 days postpartum. Data are mean ± SEM; n=7–10 per group. *P<0.05 WT vs. Corin KO mice at the same time point, as analyzed by paired t-test.

Figure 4.

LV diastolic function in pregnant WT and Corin KO mice. Mitral valve inflow pulse wave Doppler measurements were used to assess diastolic function in WT and Corin KO mice mated at 6 month of age. Echos were performed before mating (baseline) and at GD10.5, GD18.5, and 28 days postpartum. MV E: mitral valve early wave peak; MV A: mitral valve atrial wave peak; MPI: myocardial performance index; IVRT: isovolumetric relaxation time; IVCT: isovolumetric contraction time; MV e’: mitral valve early tissue wave peak. Data are mean ± SEM; n=7–10 per group. There were no statistically significant differences between WT and Corin KO mice.

Figure 5.

Heart weight and cardiomyocyte diameter in Corin KO/TgWT and KO/TgV mice. Hearts were collected at GD18.5 and compared to age-matched corresponding virgin controls at 3 months of age. (A) Heart weight normalized to tibia length. (B) Quantitative analysis of cardiomyocyte diameters. Data are mean ± SEM; n=6–8 per group. (C) Representative images of H&E-stained heart sections at 20× and 400× magnifications, bars: 500 μm (columns 1 and 3) and 20 μm (columns 2 and 4).