Original articleCXCR4 modulates contractility in adult cardiac myocytes
Introduction
Chemokines and their receptors are a relatively new class of inflammatory mediators that regulate inflammation by directing leukocytes to sites of injury. Chemokines and their receptors are up-regulated in patients with heart failure and therefore have been implicated in the development of this disease (reviewed in [1]). Contractile dysfunction is a prominent feature in heart failure, and there is an inverse relationship between chemokine levels and cardiac performance [2]. However, it is unclear whether these findings are merely coincidental or whether chemokines actually play a mechanistic role in mediating myocardial dysfunction. Furthermore, if chemokines mediate cardiac dysfunction, it is not clear whether the mechanism is via inflammatory cells or whether chemokines, through their receptors on the cardiac myocyte (CM) surface, can directly affect myocardial function.
The function of chemokines initially was thought to be limited to their migratory effects on inflammatory cells. However, as knowledge of the physiologic roles for chemokines and their receptors has markedly expanded, it is now appreciated that chemokine receptors mediate a myriad of important biological effects by activating their receptors on organs in a manner independent of inflammatory cells. CXCR4 exemplifies this concept. It is present on the mammalian heart and appears to play a critical role in cardiovascular development, in the mobilization of hematopoietic precursors and in vasculogenesis [3], [4]. CXCR4 is also a co-receptor for HIV infection and can modulate Ca2+ channel function in neuronal cell lines [5].
CXCR4 is one of several chemokine receptors that are up-regulated in patients with heart failure [2], [6], [7]. To our knowledge, it is the only chemokine receptor that has been shown to be up-regulated in the failing myocardium of patients by direct staining [6]. Other studies examining chemokine receptors in heart failure have analyzed whole heart specimens to assess mRNA levels and therefore cannot localize the cellular source of the receptor given that the heart is composed of heterogeneous cell types. In early cardiac allograft rejection, where myocardial dysfunction can be significant without an obviously discernible cause (such as significant myocyte necrosis), CXCR4 expression is also elevated [8], [9], [10], [11].
Given the increased expression of CXCR4 on dysfunctional myocardium in a variety of diseases and the specificity of CXCL12 (formerly known as stromal cell-derived factor (SDF-1)) for binding to CXCR4, this is an ideal model to demonstrate experimentally that a chemokine can directly affect myocardial function. The present study examines the effects of CXCR4 activation on myocardial contractility and explores the mechanisms at the cellular level. We demonstrate that CXCR4 negatively modulates myocardial contractility by binding its endogenous ligand, CXCL12. The mechanism of action involves an alteration of calcium (Ca2+) metabolism in response to β-adrenergic and Ca2+ stimulation in CM. These studies identify a potentially new class of receptors to target in the treatment of cardiac dysfunction.
Section snippets
Papillary muscle contractility measurements
Papillary muscles (PM) from 10-week-old male FVBN-1 mice (Jackson Laboratories) were excised, loaded onto a force-transducer (Grass Instruments) and immersed in a circulating tissue bath at 37 °C. PM were field stimulated with platinum electrodes at 2× pacing threshold amplitude with a pacing frequency of 0.3 Hz and a stimulus duration of 0.3 ms. PM were then equilibrated in a modified Tyrode solution (containing the following in mM: K+, 5.9; Na+, 135.0; Cl−, 126.0; Ca2+, 1.0; HCO3−, 15.0; PO4−
CXCR4 activation decreases PM contractility
Control and CXCL-12-treated papillary muscles were subjected to a first Ca2+ challenge to establish baseline function. They were then equilibrated at baseline Ca2+e prior to a second Ca2+ challenge. Prior to the second Ca2+ challenge, control PM were treated for 5 min with either diluent or CXCL12. Control PM demonstrated similar Log ED50 during the second (1.5 ± 0.13) and first (0.90 ± 0.23) Ca2+ challenges (p > 0.05) (Fig. 1A). In contrast, exposure to CXCL12 significantly blunted the PM response
Discussion
Heart failure is a clinical syndrome characterized by the inability of the heart to produce an adequate cardiac output [19]. A key contributor to the dysfunction may be depressed myocardial contractility [20], [21]. Studies that have examined the function of cardiac myocytes (CM) isolated from failing hearts suggest that a defect in CM contractility may contribute to the overall cardiac dysfunction [22]. The responsible agents or mechanisms, however, remain incompletely characterized.
Acknowledgments
We thank Dr. Federica del Monte for providing human cardiomyocytes and for providing insightful comments in manuscript preparation. This work was supported in part by grants from NIH: HL073458, HL054469 to ADS and HL057623, HL071763, HL078691 to RJH.
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