bcj-2022-0281 (1).pdf (30.28 MB)
PKN2 deficiency leads both to prenatal ‘congenital’ cardiomyopathy and defective angiotensin II stress responses.
journal contributionposted on 2022-07-14, 11:55 authored by Jacqueline JT Marshall, Joshua J Cull, Hajed O Alharbi, May Zaw Thin, Susanna TE Cooper, Christopher Barrington, Hannah Vanyai, Thomas Snoeks, Bernard Siow, Alejandro Suarez-Bonnet, Eleanor Herbert, Daniel J Stuckey, Angus JM Cameron, Fabrice Prin, Andrew C Cook, Simon L Priestnall, Sonia Chotani, Owen JL Rackham, Daniel Meijles, Tim Mohun, Angela Clerk, Peter J Parker
The protein kinase PKN2 is required for embryonic development and PKN2 knockout mice die as a result of failure in expansion of mesoderm, cardiac development and neural tube closure. In the adult, cardiomyocyte PKN2 and PKN1 (in combination) are required for cardiac adaptation to pressure-overload. The specific role of PKN2 in contractile cardiomyocytes during development and its role in the adult heart remain to be fully established. We used mice with cardiomyocyte-directed knockout of PKN2 or global PKN2 haploinsufficiency to assess cardiac development and function using high resolution episcopic microscopy, MRI, micro-CT and echocardiography. Biochemical and histological changes were also assessed. Cardiomyocyte-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, the requirement for PKN2 in adult mice was explored using the constitutive heterozygous PKN2 knockout. Cardiac hypertrophy resulting from hypertension induced by angiotensin II was reduced in these haploinsufficient PKN2 mice relative to wild-type littermates, with suppression of cardiomyocyte hypertrophy and cardiac fibrosis. It is concluded that cardiomyocyte 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.
Crick (Grant ID: 10117, Grant title: Mohun FC001117) Crick (Grant ID: 10130, Grant title: Parker FC001130) Crick (Grant ID: CC1107, Grant title: STP Bioinformatics & Biostatistics) Crick (Grant ID: 10020, Grant title: STP BRF - In Vivo Imaging) Crick (Grant ID: CC1061, Grant title: STP Experimental Histopathology)