title: CXCR4 modulates contractility in adult cardiac myocytes.
abstract: The inflammatory response is critical to the development and progression of heart failure. Chemokines and their receptors are a distinct class of inflammatory modulators that may play a role in mediating myocardial dysfunction in heart failure. Levels of the chemokine CXCL12, also known as stromal cell-derived factor (SDF), and its receptor, CXCR4, are elevated in patients with heart failure, and we undertook this study to determine whether this chemokine system can directly affect cardiac function in the absence of leukocytes. Murine papillary muscles and adult rat cardiac myocytes treated with CXCL12, the only identified ligand of CXCR4, demonstrate blunted inotropic responses to physiologic concentrations of calcium. The negative inotropic effects on cardiac myocytes are accompanied by a proportional diminution of calcium transients. The effects are abrogated by AMD3100, a specific CXCR4 inhibitor. Overexpression of the receptor through adenoviral infection with a CXCR4 construct accentuates the negative inotropic effects of CXCL12 on cardiac myocytes during calcium stimulation. CXCR4 activation also attenuates beta-adrenergic-mediated increases in calcium mobilization and fractional shortening in cardiac myocytes. In electrophysiologic studies, CXCL12 decreases forskolin- and isoproterenol-induced voltage-gated L-type calcium channel activation. These studies demonstrate that activation of CXCR4 results in a direct negative inotropic modulation of cardiac myocyte function. The specific mechanism of action involves alterations of calcium channel activity on the membrane. The presence of functional CXCR4 on cardiac myocytes introduces a new target for treating cardiac dysfunction.
authors.affiliation: Zena and Michael A. Wiener Cardiovascular Institute, The Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Pyo
authors.forename: Jinliang
authors.initials: J
authors.lastname: Sui
authors.forename: Ashwini
authors.initials: A
authors.lastname: Dhume
authors.forename: Julieta
authors.initials: J
authors.lastname: Palomeque
authors.forename: Burns C
authors.initials: BC
authors.lastname: Blaxall
authors.forename: George
authors.initials: G
authors.lastname: Diaz
authors.forename: James
authors.initials: J
authors.lastname: Tunstead
authors.forename: Diomedes E
authors.initials: DE
authors.lastname: Logothetis
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
authors.forename: Alison D
authors.initials: AD
authors.lastname: Schecter
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology; D004357:Drug Synergism; D005822:Genetic Vectors; D006352:Heart Ventricles / Q000378:metabolism; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D051379:Mice; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000502:physiology*; D010210:Papillary Muscles / Q000502:physiology; D051381:Rats; D019718:Receptors, CXCR4 / Q000378:metabolism* / Q000502:physiology
chemical_list: D015220:Calcium Channels; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D019718:Receptors, CXCR4; D000242:Cyclic AMP; D007545:Isoproterenol; D002118:Calcium