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MDM2 Regulation of HIF Signaling Causes Microvascular Dysfunction in Hypertrophic Cardiomyopathy
BACKGROUND: Microvasculature dysfunction is a common finding in pathologic remodeling of the heart and is thought to play an important role in the pathogenesis of hypertrophic cardiomyopathy (HCM), a disease caused by sarcomere gene mutations. We hypothesized that microvascular dysfunction in HCM wa...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Lippincott Williams & Wilkins
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10691664/ https://www.ncbi.nlm.nih.gov/pubmed/37886847 http://dx.doi.org/10.1161/CIRCULATIONAHA.123.064332 |
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author | Shridhar, Puneeth Glennon, Michael S. Pal, Soumojit Waldron, Christina J. Chetkof, Ethan J. Basak, Payel Clavere, Nicolas G. Banerjee, Dipanjan Gingras, Sebastien Becker, Jason R. |
author_facet | Shridhar, Puneeth Glennon, Michael S. Pal, Soumojit Waldron, Christina J. Chetkof, Ethan J. Basak, Payel Clavere, Nicolas G. Banerjee, Dipanjan Gingras, Sebastien Becker, Jason R. |
author_sort | Shridhar, Puneeth |
collection | PubMed |
description | BACKGROUND: Microvasculature dysfunction is a common finding in pathologic remodeling of the heart and is thought to play an important role in the pathogenesis of hypertrophic cardiomyopathy (HCM), a disease caused by sarcomere gene mutations. We hypothesized that microvascular dysfunction in HCM was secondary to abnormal microvascular growth and could occur independent of ventricular hypertrophy. METHODS: We used multimodality imaging methods to track the temporality of microvascular dysfunction in HCM mouse models harboring mutations in the sarcomere genes Mybpc3 (cardiac myosin binding protein C3) or Myh6 (myosin heavy chain 6). We performed complementary molecular methods to assess protein quantity, interactions, and post-translational modifications to identify mechanisms regulating this response. We manipulated select molecular pathways in vivo using both genetic and pharmacological methods to validate these mechanisms. RESULTS: We found that microvascular dysfunction in our HCM models occurred secondary to reduced myocardial capillary growth during the early postnatal time period and could occur before the onset of myocardial hypertrophy. We discovered that the E3 ubiquitin protein ligase MDM2 (murine double minute 2) dynamically regulates the protein stability of both HIF1α (hypoxia-inducible factor 1 alpha) and HIF2α (hypoxia-inducible factor 2 alpha)/EPAS1 (endothelial PAS domain protein 1) through canonical and noncanonical mechanisms. The resulting HIF imbalance leads to reduced proangiogenic gene expression during a key period of myocardial capillary growth. Reducing MDM2 protein levels by genetic or pharmacological methods normalized HIF protein levels and prevented the development of microvascular dysfunction in both HCM models. CONCLUSIONS: Our results show that sarcomere mutations induce cardiomyocyte MDM2 signaling during the earliest stages of disease, and this leads to long-term changes in the myocardial microenvironment. |
format | Online Article Text |
id | pubmed-10691664 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Lippincott Williams & Wilkins |
record_format | MEDLINE/PubMed |
spelling | pubmed-106916642023-12-02 MDM2 Regulation of HIF Signaling Causes Microvascular Dysfunction in Hypertrophic Cardiomyopathy Shridhar, Puneeth Glennon, Michael S. Pal, Soumojit Waldron, Christina J. Chetkof, Ethan J. Basak, Payel Clavere, Nicolas G. Banerjee, Dipanjan Gingras, Sebastien Becker, Jason R. Circulation Original Research Articles BACKGROUND: Microvasculature dysfunction is a common finding in pathologic remodeling of the heart and is thought to play an important role in the pathogenesis of hypertrophic cardiomyopathy (HCM), a disease caused by sarcomere gene mutations. We hypothesized that microvascular dysfunction in HCM was secondary to abnormal microvascular growth and could occur independent of ventricular hypertrophy. METHODS: We used multimodality imaging methods to track the temporality of microvascular dysfunction in HCM mouse models harboring mutations in the sarcomere genes Mybpc3 (cardiac myosin binding protein C3) or Myh6 (myosin heavy chain 6). We performed complementary molecular methods to assess protein quantity, interactions, and post-translational modifications to identify mechanisms regulating this response. We manipulated select molecular pathways in vivo using both genetic and pharmacological methods to validate these mechanisms. RESULTS: We found that microvascular dysfunction in our HCM models occurred secondary to reduced myocardial capillary growth during the early postnatal time period and could occur before the onset of myocardial hypertrophy. We discovered that the E3 ubiquitin protein ligase MDM2 (murine double minute 2) dynamically regulates the protein stability of both HIF1α (hypoxia-inducible factor 1 alpha) and HIF2α (hypoxia-inducible factor 2 alpha)/EPAS1 (endothelial PAS domain protein 1) through canonical and noncanonical mechanisms. The resulting HIF imbalance leads to reduced proangiogenic gene expression during a key period of myocardial capillary growth. Reducing MDM2 protein levels by genetic or pharmacological methods normalized HIF protein levels and prevented the development of microvascular dysfunction in both HCM models. CONCLUSIONS: Our results show that sarcomere mutations induce cardiomyocyte MDM2 signaling during the earliest stages of disease, and this leads to long-term changes in the myocardial microenvironment. Lippincott Williams & Wilkins 2023-10-27 2023-12-05 /pmc/articles/PMC10691664/ /pubmed/37886847 http://dx.doi.org/10.1161/CIRCULATIONAHA.123.064332 Text en © 2023 The Authors. https://creativecommons.org/licenses/by-nc-nd/4.0/Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made. |
spellingShingle | Original Research Articles Shridhar, Puneeth Glennon, Michael S. Pal, Soumojit Waldron, Christina J. Chetkof, Ethan J. Basak, Payel Clavere, Nicolas G. Banerjee, Dipanjan Gingras, Sebastien Becker, Jason R. MDM2 Regulation of HIF Signaling Causes Microvascular Dysfunction in Hypertrophic Cardiomyopathy |
title | MDM2 Regulation of HIF Signaling Causes Microvascular Dysfunction in Hypertrophic Cardiomyopathy |
title_full | MDM2 Regulation of HIF Signaling Causes Microvascular Dysfunction in Hypertrophic Cardiomyopathy |
title_fullStr | MDM2 Regulation of HIF Signaling Causes Microvascular Dysfunction in Hypertrophic Cardiomyopathy |
title_full_unstemmed | MDM2 Regulation of HIF Signaling Causes Microvascular Dysfunction in Hypertrophic Cardiomyopathy |
title_short | MDM2 Regulation of HIF Signaling Causes Microvascular Dysfunction in Hypertrophic Cardiomyopathy |
title_sort | mdm2 regulation of hif signaling causes microvascular dysfunction in hypertrophic cardiomyopathy |
topic | Original Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10691664/ https://www.ncbi.nlm.nih.gov/pubmed/37886847 http://dx.doi.org/10.1161/CIRCULATIONAHA.123.064332 |
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