Loss of cardiac myosin light chain kinase contributes to contractile dysfunction in right ventricular pressure overload
Abstract Nearly 1 in every 100 children born have a congenital heart defect. Many of these defects primarily affect the right heart causing pressure overload of the right ventricle (RV). The RV maintains function by adapting to the increased pressure; however, many of these adaptations eventually le...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2022-04-01
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| Series: | Physiological Reports |
| Subjects: | |
| Online Access: | https://doi.org/10.14814/phy2.15238 |
| _version_ | 1827581178326024192 |
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| author | Vidhya Prasad Nour Makkaoui Rohan Rajan Alisha Patel Bipul Mainali Pritha Bagchi Rhea Kumar Julia Rogers Jake Diamond Joshua T. Maxwell |
| author_facet | Vidhya Prasad Nour Makkaoui Rohan Rajan Alisha Patel Bipul Mainali Pritha Bagchi Rhea Kumar Julia Rogers Jake Diamond Joshua T. Maxwell |
| author_sort | Vidhya Prasad |
| collection | DOAJ |
| description | Abstract Nearly 1 in every 100 children born have a congenital heart defect. Many of these defects primarily affect the right heart causing pressure overload of the right ventricle (RV). The RV maintains function by adapting to the increased pressure; however, many of these adaptations eventually lead to RV hypertrophy and failure. In this study, we aim to identify the cellular and molecular mechanisms of these adaptions. We utilized a surgical animal model of pulmonary artery banding (PAB) in juvenile rats that has been shown to accurately recapitulate the physiology of right ventricular pressure overload in young hearts. Using this model, we examined changes in cardiac myocyte protein expression as a result of pressure overload with mass spectrometry 4 weeks post‐banding. We found pressure overload of the RV induced significant downregulation of cardiac myosin light chain kinase (cMLCK). Single myocyte calcium and contractility recordings showed impaired contraction and relaxation in PAB RV myocytes, consistent with the loss of cMLCK. In the PAB myocytes, calcium transients were of smaller amplitude and decayed at a slower rate compared to controls. We also identified miR‐200c, which has been shown to regulate cMLCK expression, as upregulated in the RV in response to pressure overload. These results indicate the loss of cMLCK is a critical maladaptation of the RV to pressure overload and represents a novel target for therapeutic approaches to treat RV hypertrophy and failure associated with congenital heart defects. |
| first_indexed | 2024-03-08T22:32:38Z |
| format | Article |
| id | doaj.art-c05909849adf4aa4bcb4b057ecf3e9bb |
| institution | Directory Open Access Journal |
| issn | 2051-817X |
| language | English |
| last_indexed | 2024-03-08T22:32:38Z |
| publishDate | 2022-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Physiological Reports |
| spelling | doaj.art-c05909849adf4aa4bcb4b057ecf3e9bb2023-12-18T02:20:40ZengWileyPhysiological Reports2051-817X2022-04-01107n/an/a10.14814/phy2.15238Loss of cardiac myosin light chain kinase contributes to contractile dysfunction in right ventricular pressure overloadVidhya Prasad0Nour Makkaoui1Rohan Rajan2Alisha Patel3Bipul Mainali4Pritha Bagchi5Rhea Kumar6Julia Rogers7Jake Diamond8Joshua T. Maxwell9Division of Pediatric Cardiology Department of Pediatrics Emory University School of Medicine Atlanta Georgia USADivision of Pediatric Cardiology Department of Pediatrics Emory University School of Medicine Atlanta Georgia USAEmory University College of Arts and Sciences Atlanta Georgia USAEmory University College of Arts and Sciences Atlanta Georgia USAEmory University College of Arts and Sciences Atlanta Georgia USADepartment of Biochemistry Emory University School of Medicine Atlanta Georgia USAEmory University College of Arts and Sciences Atlanta Georgia USAEmory University College of Arts and Sciences Atlanta Georgia USAEmory University College of Arts and Sciences Atlanta Georgia USADivision of Pediatric Cardiology Department of Pediatrics Emory University School of Medicine Atlanta Georgia USAAbstract Nearly 1 in every 100 children born have a congenital heart defect. Many of these defects primarily affect the right heart causing pressure overload of the right ventricle (RV). The RV maintains function by adapting to the increased pressure; however, many of these adaptations eventually lead to RV hypertrophy and failure. In this study, we aim to identify the cellular and molecular mechanisms of these adaptions. We utilized a surgical animal model of pulmonary artery banding (PAB) in juvenile rats that has been shown to accurately recapitulate the physiology of right ventricular pressure overload in young hearts. Using this model, we examined changes in cardiac myocyte protein expression as a result of pressure overload with mass spectrometry 4 weeks post‐banding. We found pressure overload of the RV induced significant downregulation of cardiac myosin light chain kinase (cMLCK). Single myocyte calcium and contractility recordings showed impaired contraction and relaxation in PAB RV myocytes, consistent with the loss of cMLCK. In the PAB myocytes, calcium transients were of smaller amplitude and decayed at a slower rate compared to controls. We also identified miR‐200c, which has been shown to regulate cMLCK expression, as upregulated in the RV in response to pressure overload. These results indicate the loss of cMLCK is a critical maladaptation of the RV to pressure overload and represents a novel target for therapeutic approaches to treat RV hypertrophy and failure associated with congenital heart defects.https://doi.org/10.14814/phy2.15238calciumcongenital heart defectheart failurehypertrophymyosin light chain kinase |
| spellingShingle | Vidhya Prasad Nour Makkaoui Rohan Rajan Alisha Patel Bipul Mainali Pritha Bagchi Rhea Kumar Julia Rogers Jake Diamond Joshua T. Maxwell Loss of cardiac myosin light chain kinase contributes to contractile dysfunction in right ventricular pressure overload Physiological Reports calcium congenital heart defect heart failure hypertrophy myosin light chain kinase |
| title | Loss of cardiac myosin light chain kinase contributes to contractile dysfunction in right ventricular pressure overload |
| title_full | Loss of cardiac myosin light chain kinase contributes to contractile dysfunction in right ventricular pressure overload |
| title_fullStr | Loss of cardiac myosin light chain kinase contributes to contractile dysfunction in right ventricular pressure overload |
| title_full_unstemmed | Loss of cardiac myosin light chain kinase contributes to contractile dysfunction in right ventricular pressure overload |
| title_short | Loss of cardiac myosin light chain kinase contributes to contractile dysfunction in right ventricular pressure overload |
| title_sort | loss of cardiac myosin light chain kinase contributes to contractile dysfunction in right ventricular pressure overload |
| topic | calcium congenital heart defect heart failure hypertrophy myosin light chain kinase |
| url | https://doi.org/10.14814/phy2.15238 |
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