PKN2 deficiency leads both to prenatal congenital cardiomyopathy and defective angiotensin II stress responses.

Marshall, J. J.; Cull, J. J.; Alharbi, H. O.; Zaw Thin, M.; Cooper, S. T.; Barrington, C.; Vanyai, H.; Snoeks, T.; Siow, B.; Suaarez-Bonnet, A.; Herbert, E.; Stuckey, D. J.; Cameron, A.; Prin, F.; Cook, A. C.; Priestnall, S. L.; Chotani, S.; Rackham, O. J.; Meijles, D. N.; Mohun, T.; Clerk, A.; Parker, P.

doi:10.1101/2022.05.24.493130

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bioRxiv · 10.1101/2022.05.24.493130

PKN2 deficiency leads both to prenatal congenital cardiomyopathy and defective angiotensin II stress responses.

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Abstract

BackgroundThe protein kinase PKN2 is required for embryonic development, and PKN2 knockout mice die as a result of failure in expansion of mesoderm tissues, cardiac development and neural tube closure. In the adult, cardiomyocyte PKN2 and PKN1 (in combination) are required for cardiac adaptation to pressure-overload. The role of PKN2 in contractile cardiomyocytes during development and its role in the adult heart remain to be fully established. MethodsWe used mice with cardiomyocyte-directed knockout of PKN2 or global PKN2 haploinsufficiency. Cardiac function and dimensions were assessed with high resolution episcopic microscopy, MRI, micro-CT and echocardiography. Biochemical and histological changes were assessed. ResultsCardiomyocyte-directed PKN2 knockout embryos displayed striking abnormalities in the compact myocardium, with frequent myocardial clefts and diverticula, ventricular septal defects and abnormal heart shape. The sub-Mendelian homozygous knockout survivors developed cardiac failure. RNASeq data showed upregulation of PKN2 in patients with dilated cardiomyopathy, suggesting an involvement in adult heart disease. Given the rarity of homozygous survivors with cardiomyocyte-specific deletion of PKN2, this was explored using mice with constitutive heterozygous PKN2 knockout. Cardiac hypertrophy resulting from hypertension induced by angiotensin II was reduced in haploinsufficient PKN2 mice relative to wild-type littermates, with suppression of cardiomyocyte hypertrophy and cardiac fibrosis. ConclusionsCardiomyocyte PKN2 is essential for heart development and formation of compact myocardium, and is also required for cardiac hypertrophy in hypertension. Thus, PKN signalling may offer therapeutic options for managing congenital and adult heart diseases.

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Marshall, J. J., Cull, J. J., Alharbi, H. O., Zaw Thin, M., Cooper, S. T., Barrington, C., Vanyai, H., Snoeks, T., Siow, B., Suaarez-Bonnet, A., Herbert, E., Stuckey, D. J., Cameron, A., Prin, F., Cook, A. C., Priestnall, S. L., Chotani, S., Rackham, O. J., Meijles, D. N., Mohun, T., Clerk, A., Parker, P.. 2022-05-24. PKN2 deficiency leads both to prenatal congenital cardiomyopathy and defective angiotensin II stress responses.. https://doi.org/10.1101/2022.05.24.493130

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