Adenosine regulation of microtubule dynamics in cardiac hypertrophy
Adenosine regulation of microtubule dynamics in cardiac hypertrophy
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DOI：
10.1152/ajpheart.00462.2009
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发表时间：
2009-08-01
影响因子：
4.8
通讯作者：
Bache, Robert J.
中科院分区：
文献类型：
--
作者：
Fassett, John T.;Xu, Xin;Bache, Robert J.
Fassett JT，Xu X，Hu X，Zhu G，French J，Chen Y，Bache RJ.腺苷对心肌肥厚中微管动力学的调节。Am J Physiol Heart Circ Physiol 297：H523-H532，2009。首次发表于2009年6月12日; doi：10.1152/ajpheart.00462.2009。有证据表明，内源性细胞外腺苷减少慢性压力超负荷小鼠的心脏肥大和心力衰竭，但腺苷发挥这些保护作用的机制尚不清楚。在这里，我们确定了腺苷在调节心脏微管细胞骨架中的新作用，这可能有助于其在超负荷心脏中的有益作用。在新生心肌细胞中，苯肾上腺素促进肥大和重组的细胞骨架，其中包括积累的肌节蛋白，微管，和结蛋白。用腺苷或稳定的腺苷类似物2-氯腺苷治疗，减少肥大，特别是减少微管的积累。在肥大的心肌细胞中，2-氯腺苷或腺苷处理优先靶向稳定的微管（含有脱酪氨酸α-微管蛋白）。与内源性腺苷降低微管稳定性的作用一致，与野生型小鼠相比，CD 73敲除小鼠（细胞外腺苷产生缺陷）心脏中的脱酪氨酸微管水平升高（195%，P < 0.05）。在响应主动脉束带，微管增加野生型小鼠的心脏，这种增加被夸大的CD 73基因敲除小鼠，与显着更大量的微管蛋白分配到冷稳定的Triton不溶性馏分。微管蛋白的这种稳定的细胞骨架组分的水平与心力衰竭的程度密切相关。与微管稳定在促进心功能障碍中的作用一致，与盐水处理的对照组相比，秋水仙碱处理的结扎带小鼠减少了肥大并改善了心功能。这些结果表明，微管有助于心功能不全，并确定，第一次，腺苷在调节心肌细胞微管动力学的作用。
Fassett JT, Xu X, Hu X, Zhu G, French J, Chen Y, Bache RJ. Adenosine regulation of microtubule dynamics in cardiac hypertrophy. Am J Physiol Heart Circ Physiol 297: H523-H532, 2009. First published June 12, 2009; doi:10.1152/ajpheart.00462.2009.-There is evidence that endogenous extracellular adenosine reduces cardiac hypertrophy and heart failure in mice subjected to chronic pressure overload, but the mechanism by which adenosine exerts these protective effects is unknown. Here, we identified a novel role for adenosine in regulation of the cardiac microtubule cytoskeleton that may contribute to its beneficial effects in the overloaded heart. In neonatal cardiomyocytes, phenylephrine promoted hypertrophy and reorganization of the cytoskeleton, which included accumulation of sarcomeric proteins, microtubules, and desmin. Treatment with adenosine or the stable adenosine analog 2-chloroadenosine, which decreased hypertrophy, specifically reduced accumulation of microtubules. In hypertrophied cardiomyocytes, 2-chloroadenosine or adenosine treatment preferentially targeted stabilized microtubules (containing detyrosinated alpha-tubulin). Consistent with a role for endogenous adenosine in reducing microtubule stability, levels of detyrosinated microtubules were elevated in hearts of CD73 knockout mice (deficient in extracellular adenosine production) compared with wild-type mice (195%, P < 0.05). In response to aortic banding, microtubules increased in hearts of wild-type mice; this increase was exaggerated in CD73 knockout mice, with significantly greater amounts of tubulin partitioning into the cold-stable Triton-insoluble fractions. The levels of this stable cytoskeletal fraction of tubulin correlated strongly with the degree of heart failure. In agreement with a role for microtubule stabilization in promoting cardiac dysfunction, colchicine treatment of aortic-banded mice reduced hypertrophy and improved cardiac function compared with saline-treated controls. These results indicate that microtubules contribute to cardiac dysfunction and identify, for the first time, a role for adenosine in regulating cardiomyocyte microtubule dynamics.