Proliferating cardiac microtubules
Proliferating cardiac microtubules
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DOI：
10.1152/ajpheart.00517.2009
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发表时间：
2009-08-01
影响因子：
4.8
通讯作者：
Cooper, George, IV
中科院分区：
文献类型：
--
作者：
Cooper, George, IV
从适应性心肌肥厚到适应不良性心力衰竭的机制一直是基础和临床心血管科学的核心目标。在心肌细胞水平上的这些研究主要集中在心脏运动，即肌丝，以及该运动的燃料，即肌浆蛋白，以及其活动的调控者，即肌浆网。虽然这些组成部分中的每一个都有多种异常，特别是在转变为心力衰竭之后，但尚不清楚这些系统中的变化是否完全解释了最早期的，因此在病因学上最重要的收缩功能恶化，这种恶化阻止了肥大心肌质量的增加无限期地补偿增加的负荷。由于肌丝不仅在上述生化环境中发挥作用，而且在由肌丝外细胞骨架定义的物理环境中发挥作用，后一个因素在20世纪80年代开始引起关注（22）。由于生理性肥大期间的心肌细胞超微结构与心力衰竭发作前的病理性肥大期间的心肌细胞超微结构差异很小（如果有的话）（19），并且由于肌丝外细胞骨架的微管组分紧密包裹肌丝，但通过标准光学或电子显微镜很难在横纹肌中辨别，1992年，我和我的同事决定研究在同等程度和持续时间的生理性肥大与病理性肥大之间，微管网络是否存在以前未被认识到的差异。事实证明是这样的，因为我们发现病理性压力过载，而不是生理性体积过载，产生了致密的微管网络，对缩短的肌节施加粘性负荷，导致收缩功能障碍，这在微管解聚时是可逆的（29，31，32）。在此后的几年中，如其他文献所述（9），我们将这一观察结果扩展到体外肌节、细胞和组织水平的多个物种的心室以及体内完整心脏（包括人类心脏）。除了这些对心细胞和心脏力学的研究之外，我们发现微管网络密度和稳定性的增加与α-和β-微管蛋白（21，28）和MAP 4（23）的上调有关，MAP 4是一种稳定微管的纤维性微管相关蛋白。此外，转基因或肥大的MAP 4上调本身显示引起微管网络致密化和相关的收缩功能和基于驱动蛋白的微管转运功能异常（6，9，25），并且通过在其他正常转基因小鼠的心脏中表达突变体β-微管蛋白的微管稳定化再现了心脏肥大微管表型（7）。需要指出的是，并不是所有在压力超负荷心脏肥大实验模型中寻找这种细胞骨架改变的研究者都重复了这些发现（2）。虽然，正如在其他地方详细审查（9），有许多因素可能是造成这种变化，一个机制为基础的解释现在可能是可用的。也就是说，由于我们手中的微管网络致密化既不是物种特异性的，也不是腔室特异性的，因此实验室间差异的一个潜在的和统一的原因很可能是，正如我们已经表明的那样，（见图8和参考文献25中的相关讨论），这种细胞骨架变化不会发生在适度的压力超负荷肥大中，而是，只发生在非常大的压力过载导致壁应力增加和…
IDENTIFYING THE MECHANISMS underlying the transition from adaptive cardiac hypertrophy to maladaptive cardiac failure has long been a central goal of basic and clinical cardiovascular science. Such studies at the level of the cardiocyte have focused largely on the cardiac motor, ie, the myofilament, as well as the fuel for that motor, ie, the mitochondrion, and the governor of its activity, ie, the sarcoplasmic reticulum. Although multiple abnormalities of each of these components have been identified, especially after the transition to heart failure, it has been much less clear that changes in these systems fully account for the earliest, and thus etiologically most important, deterioration of contractile function that prevents the increase in mass of hypertrophied myocardium from compensating indefinitely for increasing loads. Because the myofilaments function not only within a biochemical setting outlined above but also within a physical setting defined by the extramyofilament cytoskeleton, this latter factor began to attract attention in the 1980s (22). Since cardiocyte ultrastructure during physiological hypertrophy differs very little, if at all, from that during pathological hypertrophy prior to the onset of cardiac failure (19) and since the microtubule component of the extramyofilament cytoskeleton closely invests the myofilaments but is very difficult to discern in striated muscle via standard light or electron microscopy, my colleagues and I decided in 1992 to see if there was a previously unrecognized difference in the microtubule network during an equivalent degree and duration of physiological vs. pathological hypertrophy. Such turned out to be the case, in that we found that pathological pressure overloading, but not physiological volume overloading, produced a dense microtubule network that imposed a viscous load on the shortening sarcomere to cause contractile dysfunction that was reversible on microtubule depolymerization (29, 31, 32). In the years since then, as reviewed elsewhere (9), we have extended this observation to both cardiac ventricles in multiple species at the levels of sarcomere, cell, and tissue in vitro and to the intact heart, including that of humans, in vivo. Apart from these studies of cardiocyte and cardiac mechanics, we found that the increase in microtubule network density and stability is associated with upregulation of α-and β-tubulin (21, 28) and MAP4 (23), a fibrous microtubule-associated protein that stabilizes microtubules. Furthermore, transgenic or hypertrophic MAP4 upregulation itself was shown to cause microtubule network densification and associated abnormalities of contractile function and kinesin-based microtubule transport function (6, 9, 25), and microtubule stabilization via expression of a mutant β-tubulin in the hearts of otherwise normal transgenic mice reproduced the cardiac hypertrophic microtubule phenotype (7).It is, however, important to point out that not all investigators who have looked for this cytoskeletal alteration in experimental models of pressure-overload cardiac hypertrophy have replicated these findings (2). Although, as reviewed in detail elsewhere (9), there are many factors that might be responsible for this variation, a mechanism-based explanation may now be available. That is, since microtubule network densification in our hands is neither species nor chamber specific, an underlying and unifying reason for interlaboratory variation may well be that, as we have shown (see Fig. 8 and related discussion in Ref. 25), this cytoskeletal change does not happen with modest pressure-overload hypertrophy but, instead, only happens with very substantial pressure overloading leading to increased wall stress and an …