CXCR4 modulates contractility in adult cardiac myocytes
| Autor: | Julieta Palomeque, Alison D. Schecter, George A. Diaz, Jin-Liang Sui, James R. Tunstead, Diomedes E. Logothetis, Burns C. Blaxall, Robert Pyo, Ashwini Dhume, Roger J. Hajjar |
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| Rok vydání: | 2006 |
| Předmět: |
Male
Inotrope Cardiac function curve Receptors CXCR4 medicine.medical_specialty Heart Ventricles Genetic Vectors chemistry.chemical_element In Vitro Techniques Biology Calcium Article Adenoviridae Mice Internal medicine Cyclic AMP medicine Animals Myocyte Myocytes Cardiac Molecular Biology Voltage-dependent calcium channel Calcium channel Cardiac myocyte Isoproterenol Drug Synergism Papillary Muscles medicine.disease Myocardial Contraction Chemokine CXCL12 Rats Endocrinology chemistry Heart failure Calcium Channels Cardiology and Cardiovascular Medicine Chemokines CXC |
| Zdroj: | Journal of Molecular and Cellular Cardiology. 41:834-844 |
| ISSN: | 0022-2828 |
| DOI: | 10.1016/j.yjmcc.2006.08.008 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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