CXCR4 gene transfer prevents pressure overload induced heart failure.
CXCR4 gene transfer prevents pressure overload induced heart failure.
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DOI：
10.1016/j.yjmcc.2012.05.016
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发表时间：
2012-08
影响因子：
5
通讯作者：
Tarzami ST
中科院分区：
文献类型：
--
作者：
Larocca TJ;Jeong D;Kohlbrenner E;Lee A;Chen J;Hajjar RJ;Tarzami ST
干细胞和基因疗法正被用作心肌梗死后修复受损心脏组织的策略，以预防心力衰竭。趋化因子受体4（CXCR 4）及其配体CXCL 12在急性心肌梗死后干细胞募集中起关键作用。尽管祖细胞通过CXCL 12/CXCR 4轴的迁移已被充分表征，但对CXCR 4介导的心脏肥大和衰竭调节的分子机制知之甚少。我们使用基因治疗来测试CXCR 4基因递送对由于压力超负荷引起的不利心室重构的影响。我们使用携带CXCR 4基因的亲心腺相关病毒载体（AAV 9）评估了经主动脉缩窄（TAC）期间心脏CXCR 4过表达的影响。通过超声心动图和体内血流动力学测定，在压力超负荷小鼠中CXCR 4的心脏过表达可防止心室重塑，保持毛细血管密度并维持功能。在分离的成年大鼠心肌细胞中，CXCL 12处理防止异丙肾上腺素诱导的肥大，并中断钙调神经磷酸酶/NFAT途径。最后，在健康心肌细胞中鉴定了一种涉及L型钙通道、β2-腺受体和CXCR 4的复合物（Cav1.2/β2AR/CXCR 4），并显示其在心力衰竭时解离。通过基因转移向心脏施用CXCR 4可预防压力超负荷诱导的心力衰竭。CXCR 4参与Cav1.2-β2AR调节复合物的鉴定为CXCR 4调节心肌细胞中钙稳态和慢性压力超负荷反应的机制提供了进一步的见解。这些结果共同表明AAV9.CXCR4基因治疗是充血性心力衰竭的潜在治疗方法。
Stem cell and gene therapies are being pursued as strategies for repairing damaged cardiac tissue following myocardial infarction in an attempt to prevent heart failure. The chemokine receptor-4 (CXCR4) and its ligand, CXCL12, play a critical role in stem cell recruitment post-acute myocardial infarction. Whereas progenitor cell migration via the CXCL12/CXCR4 axis is well characterized, little is known about the molecular mechanisms of CXCR4 mediated modulation of cardiac hypertrophy and failure. We used gene therapy to test the effects of CXCR4 gene delivery on adverse ventricular remodeling due to pressure overload. We assessed the effect of cardiac overexpression of CXCR4 during trans-aortic constriction (TAC) using a cardiotropic adeno-associated viral vector (AAV9) carrying the CXCR4 gene. Cardiac overexpression of CXCR4 in mice with pressure overload prevented ventricular remodeling, preserved capillary density and maintained function as determined by echocardiography and in vivo hemodynamics. In isolated adult rat cardiac myocytes, CXCL12 treatment prevented isoproterenol induced hypertrophy and interrupted the calcineurin/NFAT pathway. Finally, a complex involving the L-type calcium channel, β2-adenoreceptor, and CXCR4 (Cav1.2/β2AR/CXCR4) was identified in healthy cardiac myocytes and was shown to dissociate as a consequence of heart failure. CXCR4 administered to the heart via gene transfer prevents pressure overload induced heart failure. The identification of CXCR4 participation in a Cav1.2-β2AR regulatory complex provides further insight into the mechanism by which CXCR4 modulates calcium homeostasis and chronic pressure overload responses in the cardiac myocyte. Together these results suggest AAV9.CXCR4 gene therapy is a potential therapeutic approach for congestive heart failure.
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影响因子：
37.8
作者：
Suckau L;Fechner H;Chemaly E;Krohn S;Hadri L;Kockskämper J;Westermann D;Bisping E;Ly H;Wang X;Kawase Y;Chen J;Liang L;Sipo I;Vetter R;Weger S;Kurreck J;Erdmann V;Tschope C;Pieske B;Lebeche D;Schultheiss HP;Hajjar RJ;Poller WC
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Poller WC
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通讯作者：
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影响因子：
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作者：
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通讯作者：
Gorelik, Julia
影响因子：
4.4
作者：
Vlahakis, SR;Villasis-Keever, A;Paya, CV
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Paya, CV