Deletion of CXCR4 in cardiomyocytes exacerbates cardiac dysfunction following isoproterenol administration.
Deletion of CXCR4 in cardiomyocytes exacerbates cardiac dysfunction following isoproterenol administration.
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DOI：
10.1038/gt.2014.23
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发表时间：
2014-05
期刊：
影响因子：
5.1
通讯作者：
Tarzami, S. T.
中科院分区：
文献类型：
--
作者：
Wang, E. R.;Jarrah, A. A.;Benard, L.;Chen, J.;Schwarzkopf, M.;Hadri, L.;Tarzami, S. T.
α-和β-肾上腺素能受体信号传导的改变与心脏肥大和衰竭相关。据报道，基质细胞衍生因子 1α (SDF-1α) 及其同源受体 CXCR4 可通过将干细胞动员到受损组织中来介导损伤后的心脏保护作用。然而，关于 SDF-1/CXCR4 是否在病理性肥大后诱导急性保护以及如果是，通过什么分子机制，人们知之甚少。我们之前曾报道过 CXCR4 与 β2 肾上腺素受体发生物理相互作用并调节其下游信号传导。在这里，我们发现 CXCR4 表达可以预防 β-肾上腺素能受体诱导的肥大。通过植入给予异丙肾上腺素的皮下渗透泵来刺激心脏β-肾上腺素能受体，并且使用Cre-loxP介导的基因重组选择性地消除心肌细胞中的CXCR4表达。 CXCR4 敲除小鼠表现出缩短分数和射血分数恶化。 CXCR4 消融通过上调细胞凋亡标记物和降低线粒体功能，增加对异丙肾上腺素诱导的心力衰竭的易感性；心脏功能下降，纤维化增加。此外，使用心肌腺相关病毒 9 (AAV9) 载体可以挽救 CXCR4 表达。 CXCR4基因转移减少了心脏凋亡信号，改善了线粒体功能，并导致心脏功能恢复。我们的结果首次证明 SDF-1/CXCR4 信号通过调节体内 β-肾上腺素能受体信号介导急性心脏保护作用。
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 down stream 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 while fibrosis increases. Additionally, CXCR4 expression was rescued with the use of cardiotropic Adeno-associated viral-9 (AAV9) 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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影响因子：
20.1
作者：
Agarwal, Udit;Ghalayini, Wael;Penn, Marc S.
通讯作者：
Penn, Marc S.
影响因子：
5
作者：
Chen, CG;Li, J;Liu-Chen, LY
通讯作者：
Liu-Chen, LY
DOI：
10.1073/pnas.95.16.9448
发表时间：
1998-08-04
影响因子：
11.1
作者：
Ma, Q;Jones, D;Springer, TA
通讯作者：
Springer, TA
影响因子：
37.8
作者：
Dong, Feng;Harvey, James;Penn, Marc S.
通讯作者：
Penn, Marc S.
影响因子：
6
作者：
Jaski, Brian E.;Jessup, Mariell L.;Mancini, Donna M.;Cappola, Thomas P.;Pauly, Daniel F.;Greenberg, Barry;Borow, Kenneth;Dittrich, Howard;Zsebo, Krisztina M.;Hajjar, Roger J.
通讯作者：
Hajjar, Roger J.