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Deletion of CXCR4 in cardiomyocytes exacerbates cardiac dysfunction following isoproterenol administration

Gene Therapy volume 21, pages 496–506 (2014)Cite this article

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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.

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Acknowledgements

This study was supported in part by the American Heart Association (grant GRNT4180006 to STT) and the National Institutes of Health (grant K02HL102163-01 to STT). We would like to thank Drs Roger Hajjar and Antoine Chaanine for their helpful advice and suggestions throughout the data analysis.

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Authors and Affiliations

  1. Department of Medicine, Division of Cardiovascular Research Center, Mount Sinai School of Medicine, New York, NY, USA

    E R Wang, A A Jarrah, L Benard, J Chen, M Schwarzkopf, L Hadri & S T Tarzami

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  1. E R Wang
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Correspondence to S T Tarzami.

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Wang, E., Jarrah, A., Benard, L. et al. Deletion of CXCR4 in cardiomyocytes exacerbates cardiac dysfunction following isoproterenol administration. Gene Ther 21, 496–506 (2014). https://doi.org/10.1038/gt.2014.23

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