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Deletion of CXCR4 in cardiomyocytes exacerbates cardiac dysfunction following isoproterenol administration
Altered alpha- and beta-adrenergic receptor signaling is associated with cardiac hypertrophy and failure. Stromal cell-derived factor-1α (SDF-1α) and its cognate receptor CXCR4 have been reported to mediate cardioprotection after injury through the mobilization of stem cells into injured tissue. How...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4016112/ https://www.ncbi.nlm.nih.gov/pubmed/24646609 http://dx.doi.org/10.1038/gt.2014.23 |
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author | Wang, ER Jarrah, AA Benard, L Chen, J Schwarzkopf, M Hadri, L Tarzami, ST |
author_facet | Wang, ER Jarrah, AA Benard, L Chen, J Schwarzkopf, M Hadri, L Tarzami, ST |
author_sort | Wang, ER |
collection | PubMed |
description | Altered alpha- and beta-adrenergic receptor signaling is associated with cardiac hypertrophy and failure. Stromal cell-derived factor-1α (SDF-1α) and its cognate receptor CXCR4 have been reported to mediate cardioprotection after injury through the mobilization of stem cells into injured tissue. However, little is known regarding whether SDF-1/CXCR4 induces acute protection following pathological hypertrophy and if so, by what molecular mechanism. We have previously reported that CXCR4 physically interacts with the beta-2 adrenergic receptor and modulates its down stream signaling. Here we have shown that CXCR4 expression prevents beta-adrenergic receptor induced hypertrophy. Cardiac beta-adrenergic receptors were stimulated with the implantation of a subcutaneous osmotic pump administrating isoproterenol and CXCR4 expression was selectively abrogated in cardiomyocytes using Cre-loxP-mediated gene recombination. CXCR4 knockout mice showed worsened fractional shortening and ejection fraction. CXCR4 ablation increased susceptibility to isoproterenol-induced heart failure, by upregulating apoptotic markers and reducing mitochondrial function; cardiac function decreases while fibrosis increases. Additionally, CXCR4 expression was rescued with the use of cardiotropic Adeno-associated viral-9 (AAV9) vectors. CXCR4 gene transfer reduced cardiac apoptotic signaling, improved mitochondrial function and resulted in a recovered cardiac function. Our results represent the first evidence that SDF-1/CXCR4 signaling mediates acute cardioprotection through modulating beta-adrenergic receptor signaling in vivo. |
format | Online Article Text |
id | pubmed-4016112 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
record_format | MEDLINE/PubMed |
spelling | pubmed-40161122014-11-01 Deletion of CXCR4 in cardiomyocytes exacerbates cardiac dysfunction following isoproterenol administration Wang, ER Jarrah, AA Benard, L Chen, J Schwarzkopf, M Hadri, L Tarzami, ST Gene Ther Article Altered alpha- and beta-adrenergic receptor signaling is associated with cardiac hypertrophy and failure. Stromal cell-derived factor-1α (SDF-1α) and its cognate receptor CXCR4 have been reported to mediate cardioprotection after injury through the mobilization of stem cells into injured tissue. However, little is known regarding whether SDF-1/CXCR4 induces acute protection following pathological hypertrophy and if so, by what molecular mechanism. We have previously reported that CXCR4 physically interacts with the beta-2 adrenergic receptor and modulates its down stream signaling. Here we have shown that CXCR4 expression prevents beta-adrenergic receptor induced hypertrophy. Cardiac beta-adrenergic receptors were stimulated with the implantation of a subcutaneous osmotic pump administrating isoproterenol and CXCR4 expression was selectively abrogated in cardiomyocytes using Cre-loxP-mediated gene recombination. CXCR4 knockout mice showed worsened fractional shortening and ejection fraction. CXCR4 ablation increased susceptibility to isoproterenol-induced heart failure, by upregulating apoptotic markers and reducing mitochondrial function; cardiac function decreases while fibrosis increases. Additionally, CXCR4 expression was rescued with the use of cardiotropic Adeno-associated viral-9 (AAV9) vectors. CXCR4 gene transfer reduced cardiac apoptotic signaling, improved mitochondrial function and resulted in a recovered cardiac function. Our results represent the first evidence that SDF-1/CXCR4 signaling mediates acute cardioprotection through modulating beta-adrenergic receptor signaling in vivo. 2014-03-20 2014-05 /pmc/articles/PMC4016112/ /pubmed/24646609 http://dx.doi.org/10.1038/gt.2014.23 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Wang, ER Jarrah, AA Benard, L Chen, J Schwarzkopf, M Hadri, L Tarzami, ST Deletion of CXCR4 in cardiomyocytes exacerbates cardiac dysfunction following isoproterenol administration |
title | Deletion of CXCR4 in cardiomyocytes exacerbates cardiac dysfunction following isoproterenol administration |
title_full | Deletion of CXCR4 in cardiomyocytes exacerbates cardiac dysfunction following isoproterenol administration |
title_fullStr | Deletion of CXCR4 in cardiomyocytes exacerbates cardiac dysfunction following isoproterenol administration |
title_full_unstemmed | Deletion of CXCR4 in cardiomyocytes exacerbates cardiac dysfunction following isoproterenol administration |
title_short | Deletion of CXCR4 in cardiomyocytes exacerbates cardiac dysfunction following isoproterenol administration |
title_sort | deletion of cxcr4 in cardiomyocytes exacerbates cardiac dysfunction following isoproterenol administration |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4016112/ https://www.ncbi.nlm.nih.gov/pubmed/24646609 http://dx.doi.org/10.1038/gt.2014.23 |
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