Runx1 Deficiency Protects Against Adverse Cardiac Remodeling After Myocardial Infarction
| Autor: | McCarroll, Charlotte S., He, Weihong, Foote, Kirsty, Bradley, Ashley, Mcglynn, Karen, Vidler, Francesca, Nixon, Colin, Nather, Katrin, Fatta, Caroline, Riddell, Alexandra, Bowman, Peter, Elliott, Elspeth B., Bell, Margaret, Hawksby, Catherine, MacKenzie, Scott M., Morrison, Liam J., Terry, Anne, Blyth, Karen, Smith, Godfrey L., McBride, Martin W., Kubin, Thomas, Braun, Thomas, Nicklin, Stuart A., Cameron, Ewan R., Loughrey, Christopher M. |
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| Rok vydání: | 2016 |
| Předmět: |
Time Factors
Myocardial Infarction Ventricular Function Left Sarcoplasmic Reticulum Calcium-Transporting ATPases Original Research Articles Animals Myocytes Cardiac Calcium Signaling Phosphorylation Cells Cultured Mice Knockout calcium Ventricular Remodeling Calcium-Binding Proteins Cyclic AMP-Dependent Protein Kinases Myocardial Contraction sarcoplasmic reticulum Mice Inbred C57BL Disease Models Animal cardiac remodeling ventricular Core Binding Factor Alpha 2 Subunit ComputingMethodologies_DOCUMENTANDTEXTPROCESSING Rabbits |
| Zdroj: | Circulation BASE-Bielefeld Academic Search Engine |
| ISSN: | 1524-4539 0009-7322 |
| Popis: | Supplemental Digital Content is available in the text. Background: Myocardial infarction (MI) is a leading cause of heart failure and death worldwide. Preservation of contractile function and protection against adverse changes in ventricular architecture (cardiac remodeling) are key factors to limiting progression of this condition to heart failure. Consequently, new therapeutic targets are urgently required to achieve this aim. Expression of the Runx1 transcription factor is increased in adult cardiomyocytes after MI; however, the functional role of Runx1 in the heart is unknown. Methods: To address this question, we have generated a novel tamoxifen-inducible cardiomyocyte-specific Runx1-deficient mouse. Mice were subjected to MI by means of coronary artery ligation. Cardiac remodeling and contractile function were assessed extensively at the whole-heart, cardiomyocyte, and molecular levels. Results: Runx1-deficient mice were protected against adverse cardiac remodeling after MI, maintaining ventricular wall thickness and contractile function. Furthermore, these mice lacked eccentric hypertrophy, and their cardiomyocytes exhibited markedly improved calcium handling. At the mechanistic level, these effects were achieved through increased phosphorylation of phospholamban by protein kinase A and relief of sarco/endoplasmic reticulum Ca2+-ATPase inhibition. Enhanced sarco/endoplasmic reticulum Ca2+-ATPase activity in Runx1-deficient mice increased sarcoplasmic reticulum calcium content and sarcoplasmic reticulum–mediated calcium release, preserving cardiomyocyte contraction after MI. Conclusions: Our data identified Runx1 as a novel therapeutic target with translational potential to counteract the effects of adverse cardiac remodeling, thereby improving survival and quality of life among patients with MI. |
| Databáze: | OpenAIRE |
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