Marshall, Jacqueline Jt;
Cull, Joshua J;
Alharbi, Hajed O;
Zaw Thin, May;
Cooper, Susanna Te;
Barrington, Christopher;
Vanyai, Hannah;
... Parker, Peter J; + view all
(2022)
PKN2 deficiency leads both to prenatal congenital cardiomyopathy and defective angiotensin II stress responses.
Biochemical Journal
, Article BCJ20220281. 10.1042/BCJ20220281.
(In press).
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Abstract
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.
| Type: | Article |
|---|---|
| Title: | PKN2 deficiency leads both to prenatal congenital cardiomyopathy and defective angiotensin II stress responses |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1042/BCJ20220281 |
| Publisher version: | https://doi.org/10.1042/BCJ20220281 |
| Language: | English |
| Additional information: | Copyright 2022 The Author(s) This is an Accepted Manuscript; not the final Version of Record. You are encouraged to use the final Version of Record that, when published, will replace this manuscript and be freely available under a Creative Commons licence. |
| Keywords: | Protein Kinase N, cardiac development, cardiomyopathy, stress response |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Department of Imaging UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10151856 |
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