Targeted inhibition of p38 MAPK promotes hypertrophic cardiomyopathy through upregulation of calcineurin-NEAT signaling
Targeted inhibition of p38 MAPK promotes hypertrophic cardiomyopathy through upregulation of calcineurin-NEAT signaling
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DOI：
10.1172/jci200317295
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发表时间：
2003-05-01
影响因子：
15.9
通讯作者：
Molkentin, JD
中科院分区：
文献类型：
--
作者：
Braz, JC;Bueno, OF;Molkentin, JD
在几乎所有类型的真核细胞中，MAPK都是生长和应激刺激的重要转导。在哺乳动物的心脏中，MAPK信号通路被假设为调节心肌细胞的生长，以响应发育信号或生理和病理刺激。在这里，我们产生了心脏特异的转基因小鼠，表达了p38pha、MKK3或MKK6的显性-负性突变。值得注意的是，心脏p38活性的减弱导致了心脏的渐进性生长反应和肌病，这与酶抑制的程度有关。此外，显性阴性的P38A、MKK3和MKK6转基因小鼠在主动脉缩窄、Ang II输注、异丙肾上腺素输注或苯肾上腺素输注14天后均表现出心肌肥厚增强。通过观察到显性负P38A直接增强激活的T细胞核因子(NFAT)转录活性及其核转位，提出了这种增强生长曲线的机制。在体内，依赖于NFAT的荧光素酶报告基因转基因小鼠在显性负性P38A转基因存在的情况下，在心肌肥厚开始前后表现出增强的激活。更重要的是，钙调神经磷酸酶Aβ基因的遗传破坏挽救了肥厚性心肌病，并抑制了p38抑制小鼠的功能能力。总之，这些观察表明，心脏中p38信号的减少通过钙调神经磷酸酶-NFAT信号增强的机制促进了心肌细胞的生长。
The MAPKs are important transducers of growth and stress stimuli in virtually all eukaryotic cell types. In the mammalian heart, MAPK signaling pathways have been hypothesized to regulate myocyte growth in response to developmental signals or physiologic and pathologic stimuli. Here we generated cardiac-specific transgenic mice expressing dominant-negative mutants of p38alpha, MKK3, or MKK6. Remarkably, attenuation of cardiac p38 activity produced a progressive growth response and myopathy in the heart that correlated with the degree of enzymatic inhibition. Moreover, dominant-negative p38a, MKK3, and MKK6 transgenic mice each showed enhanced cardiac hypertrophy following aortic banding, Ang II infusion, isoproterenol infusion, or phenylephrine infusion for 14 days. A mechanism underlying this enhanced-growth profile was suggested by the observation that dominant-negative p38a directly augmented nuclear factor of activated T cells (NFAT) transcriptional activity and its nuclear translocation. In vivo, NFAT-dependent luciferase reporter transgenic mice showed enhanced activation in the presence of the dominant-negative p38a transgene before and after the onset of cardiac hypertrophy. More significantly, genetic disruption of the calcineurin Abeta gene rescued hypertrophic cardiomyopathy and depressed functional capacity observed in p38-inhibited mice. Collectively, these observations indicate that reduced p38 signaling in the heart promotes myocyte growth through a mechanism involving enhanced calcineurin-NFAT signaling.