The pathophysiological role of stretch activated channel(TRPV2) in cardiomypathy and heart failure

肌营养不良症是一种严重的骨骼肌退行性疾病，以进行性肌肉无力为特征。这种疾病的一个亚群是由编码抗肌营养不良蛋白-糖蛋白复合体的一种成分的基因缺陷引起的，导致细胞膜完整性和/或稳定性的显著破坏，从而导致胞浆钙离子浓度持续增加([Ca^lt；2+gt；]i)。在这里，我们证明了在两种动物模型中，肌营养不良在很大程度上是通过对瞬时受体电位阳离子通道TRPV2的显性-负性抑制来预防的，该通道是钙离子进入途径的主要候选者。这两种动物模型分别是Dystrophin缺陷型mdx小鼠和δ肌聚糖缺陷型。当在肌肉中表达TRPV2突变体的转基因(TG)小鼠与mdx小鼠杂交时，内源性TRPV2以显性-负性方式抑制肌肉纤维[Ca^&lt；2+&gt；]_i的增加明显减少。此外，表征营养不良病理的组织学、生化和生理指标，如中央核数量增加和纤维大小变异/纤维化/凋亡，血清肌酸激酶水平升高和肌肉性能下降，都在MDX/TG小鼠中得到改善。在感染了携带突变TRPV2的腺病毒的BIO14.6仓鼠的肌肉中也观察到了类似的有益效果。我们认为，TRPV2是导致[Ca^&lt；2+&gt；]_i持续升高和肌肉退变的主要钙通道，是治疗肌营养不良的一个有前景的靶点。

Muscular dystrophy is a severe degenerative disorder of skeletal muscles characterized by progressive muscle weakness. One subgroup of this disease is caused by a defect in the gene encoding one of the components of the dystrophin-glycoprotein complex, resulting in significant disruption of membrane integrity and/or stability, and consequently a sustained increase in the cytosolic Ca^<2+> concentration([Ca^<2+>]_i). Here, we demonstrate that muscular dystrophy in two animal models, dystrophin-deficient mdx mice and δ-sarcoglycan-deficient BIO14.6 hamsters, are largely prevented by dominant-negative inhibition of a transient receptor potential cation channel TRPV2, a principal candidate for Ca^<2+>-entry pathways. When transgenic(Tg) mice expressing a TRPV2 mutant in muscle were crossed with mdx mice, the [Ca^<2+>]_i increase in muscle fibers was markedly reduced by inhibition of endogenous TRPV2 in a dominant-negative manner. Furthermore, histological, biochemical and physiological indices characterizing dystrophic pathology, such as increased number of central nuclei and fiber size variability/fibrosis/apoptosis, elevated creatine kinase level in serum and reduced muscle performance, were all ameliorated in the mdx/Tg mice. Similar beneficial effects were also observed in muscles of BIO14.6 hamsters infected with adenovirus carrying mutant TRPV2. We propose that TRPV2 is a principal Ca^<2+>-entry route leading to sustained [Ca^<2+>]_i increase and muscle degeneration, and is a promising therapeutic target for treatment of muscular dystrophy.