Deletion of CXCR4 in cardiomyocytes exacerbates cardiac dysfunction following isoproterenol administration
| Autor: | Sima T. Tarzami, L Hadri, Edward R. Wang, M Schwarzkopf, L Benard, Andrew A. Jarrah, Jiqiu Chen |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Cardiac function curve
medicine.medical_specialty Receptors CXCR4 Cardiotonic Agents Genetic Vectors heart failure chemokines Apoptosis Cardiomegaly adeno-associated virus Biology Article Muscle hypertrophy Gene Knockout Techniques Glycogen Synthase Kinase 3 Mice Internal medicine Receptors Adrenergic beta Genetics medicine Myocyte Animals Myocytes Cardiac gene delivery Receptor Molecular Biology GSK3B Cardioprotection Mice Knockout Glycogen Synthase Kinase 3 beta Gene Transfer Techniques Isoproterenol Stroke Volume Adrenergic beta-Agonists Dependovirus Fibrosis Chemokine CXCL12 3. Good health Cell biology Mitochondria Mice Inbred C57BL Endocrinology Knockout mouse Molecular Medicine Signal transduction cardiac remodeling Signal Transduction |
| Zdroj: | Gene therapy |
| ISSN: | 1476-5462 0969-7128 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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