title: Deletion of CXCR4 in cardiomyocytes exacerbates cardiac dysfunction following isoproterenol administration.
abstract: 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 downstream 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 whereas fibrosis increases. In addition, CXCR4 expression was rescued with the use of cardiotropic adeno-associated viral-9 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.
authors.affiliation: Department of Medicine, Division of Cardiovascular Research Center, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: E R
authors.initials: ER
authors.lastname: Wang
authors.affiliation: Department of Medicine, Division of Cardiovascular Research Center, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Jarrah
authors.affiliation: Department of Medicine, Division of Cardiovascular Research Center, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: L
authors.initials: L
authors.lastname: Benard
authors.affiliation: Department of Medicine, Division of Cardiovascular Research Center, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Medicine, Division of Cardiovascular Research Center, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: M
authors.initials: M
authors.lastname: Schwarzkopf
authors.affiliation: Department of Medicine, Division of Cardiovascular Research Center, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: L
authors.initials: L
authors.lastname: Hadri
authors.affiliation: Department of Medicine, Division of Cardiovascular Research Center, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: S T
authors.initials: ST
authors.lastname: Tarzami
mesh_terms: D000318:Adrenergic beta-Agonists / Q000008:administration & dosage* / Q000009:adverse effects; D000818:Animals; D017209:Apoptosis; D006332:Cardiomegaly / Q000139:chemically induced / Q000235:genetics*; D002316:Cardiotonic Agents; D054377:Chemokine CXCL12 / Q000235:genetics; D000229:Dependovirus / Q000235:genetics; D005355:Fibrosis / Q000139:chemically induced / Q000235:genetics; D055786:Gene Knockout Techniques; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000096:biosynthesis; D000071679:Glycogen Synthase Kinase 3 beta; D006333:Heart Failure / Q000139:chemically induced / Q000235:genetics*; D007545:Isoproterenol / Q000008:administration & dosage* / Q000009:adverse effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction; D013318:Stroke Volume / Q000187:drug effects / Q000235:genetics
chemical_list: D000318:Adrenergic beta-Agonists; C514936:CXCR4 protein, mouse; D002316:Cardiotonic Agents; D054377:Chemokine CXCL12; D011943:Receptors, Adrenergic, beta; D019718:Receptors, CXCR4; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D007545:Isoproterenol