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PKN2 deficiency leads both to prenatal ‘congenital’ cardiomyopathy and defective angiotensin II stress responses
The protein kinase PKN2 is required for embryonic development and PKN2 knockout mice die as a result of failure in the 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-overlo...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Portland Press Ltd.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9342899/ https://www.ncbi.nlm.nih.gov/pubmed/35730579 http://dx.doi.org/10.1042/BCJ20220281 |
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author | Marshall, Jacqueline J.T. Cull, Joshua J. Alharbi, Hajed O. Zaw Thin, May Cooper, Susanna T.E. Barrington, Christopher Vanyai, Hannah Snoeks, Thomas Siow, Bernard Suáarez-Bonnet, Alejandro Herbert, Eleanor Stuckey, Daniel J. Cameron, Angus J.M. Prin, Fabrice Cook, Andrew C. Priestnall, Simon L. Chotani, Sonia Rackham, Owen J. L. Meijles, Daniel N. Mohun, Tim Clerk, Angela Parker, Peter J. |
author_facet | Marshall, Jacqueline J.T. Cull, Joshua J. Alharbi, Hajed O. Zaw Thin, May Cooper, Susanna T.E. Barrington, Christopher Vanyai, Hannah Snoeks, Thomas Siow, Bernard Suáarez-Bonnet, Alejandro Herbert, Eleanor Stuckey, Daniel J. Cameron, Angus J.M. Prin, Fabrice Cook, Andrew C. Priestnall, Simon L. Chotani, Sonia Rackham, Owen J. L. Meijles, Daniel N. Mohun, Tim Clerk, Angela Parker, Peter J. |
author_sort | Marshall, Jacqueline J.T. |
collection | PubMed |
description | The protein kinase PKN2 is required for embryonic development and PKN2 knockout mice die as a result of failure in the 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 up-regulation 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 the 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. |
format | Online Article Text |
id | pubmed-9342899 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Portland Press Ltd. |
record_format | MEDLINE/PubMed |
spelling | pubmed-93428992022-08-09 PKN2 deficiency leads both to prenatal ‘congenital’ cardiomyopathy and defective angiotensin II stress responses Marshall, Jacqueline J.T. Cull, Joshua J. Alharbi, Hajed O. Zaw Thin, May Cooper, Susanna T.E. Barrington, Christopher Vanyai, Hannah Snoeks, Thomas Siow, Bernard Suáarez-Bonnet, Alejandro Herbert, Eleanor Stuckey, Daniel J. Cameron, Angus J.M. Prin, Fabrice Cook, Andrew C. Priestnall, Simon L. Chotani, Sonia Rackham, Owen J. L. Meijles, Daniel N. Mohun, Tim Clerk, Angela Parker, Peter J. Biochem J Cardiovascular System & Vascular Biology The protein kinase PKN2 is required for embryonic development and PKN2 knockout mice die as a result of failure in the 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 up-regulation 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 the 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. Portland Press Ltd. 2022-07-12 /pmc/articles/PMC9342899/ /pubmed/35730579 http://dx.doi.org/10.1042/BCJ20220281 Text en © 2022 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Cardiovascular System & Vascular Biology Marshall, Jacqueline J.T. Cull, Joshua J. Alharbi, Hajed O. Zaw Thin, May Cooper, Susanna T.E. Barrington, Christopher Vanyai, Hannah Snoeks, Thomas Siow, Bernard Suáarez-Bonnet, Alejandro Herbert, Eleanor Stuckey, Daniel J. Cameron, Angus J.M. Prin, Fabrice Cook, Andrew C. Priestnall, Simon L. Chotani, Sonia Rackham, Owen J. L. Meijles, Daniel N. Mohun, Tim Clerk, Angela Parker, Peter J. PKN2 deficiency leads both to prenatal ‘congenital’ cardiomyopathy and defective angiotensin II stress responses |
title | PKN2 deficiency leads both to prenatal ‘congenital’ cardiomyopathy and defective angiotensin II stress responses |
title_full | PKN2 deficiency leads both to prenatal ‘congenital’ cardiomyopathy and defective angiotensin II stress responses |
title_fullStr | PKN2 deficiency leads both to prenatal ‘congenital’ cardiomyopathy and defective angiotensin II stress responses |
title_full_unstemmed | PKN2 deficiency leads both to prenatal ‘congenital’ cardiomyopathy and defective angiotensin II stress responses |
title_short | PKN2 deficiency leads both to prenatal ‘congenital’ cardiomyopathy and defective angiotensin II stress responses |
title_sort | pkn2 deficiency leads both to prenatal ‘congenital’ cardiomyopathy and defective angiotensin ii stress responses |
topic | Cardiovascular System & Vascular Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9342899/ https://www.ncbi.nlm.nih.gov/pubmed/35730579 http://dx.doi.org/10.1042/BCJ20220281 |
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