Molecular alteration of Cav1.2 calcium channel in chronic myocardial infarction
Molecular alteration of Cav1.2 calcium channel in chronic myocardial infarction
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DOI：
10.1007/s00424-009-0652-4
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发表时间：
2009-08-01
影响因子：
4.5
通讯作者：
Soong, Tuck Wah
中科院分区：
文献类型：
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作者：
Liao, Ping;Li, Guang;Soong, Tuck Wah
Ca（v）1.2通道在心肌兴奋-收缩偶联中起重要作用。Ca（v）1.2通道的选择性剪接可以产生通道特性的广泛表型变异。在慢性心肌梗死大鼠模型中，我们研究了Ca（v）1.2通道是否可以改变选择性剪接外显子的使用，以产生功能变体。结扎大鼠左前降支建立心肌梗死模型。结扎后8周，我们发现在瘢痕区，一些选择性剪接外显子的表达发生了变化。逆转录聚合酶链反应、激光捕获显微切割和免疫组化检测到9号外显子 * 包含和33号外显子缺失的比例增加并定位于存活的心肌细胞。野生型Delta 9*/33（缺失外显子9* 和包含外显子33）通道在瘢痕区域大大减少，其他几种亚型增加。重要的是，在瘢痕区域中产生了新的9*/Delta 33（包含外显子9* 和缺失外显子33）通道。电生理研究表明，瘢痕区发现的通道在HEK 293细胞中表达时，激活和失活电位均表现出超极化偏移。Ca（v）1.2通道的变化可能在维持肌肉兴奋性和收缩性方面起作用，也可能参与骨骼肌的形成。
Ca(v)1.2 channels are important for excitation-contraction coupling of cardiac muscles. Alternative splicing of Ca(v)1.2 channels could produce extensive phenotypic variations of channel properties. In a rat model of chronic myocardial infarction, we investigated whether Ca(v)1.2 channels may alter the use of alternatively spliced exons to generate functional variants. A myocardial infarction model on rat was generated by ligating the left anterior descending artery. Eight weeks after ligation, we found that in the scar region, the expression of a number of alternatively spliced exons were changed. The proportions of exon 9* inclusion and exon 33 deletion were detected to increase and localize at the surviving cardiac muscle cells with reverse transcriptase polymerase chain reaction, laser capture microdissection, and immunostaining. The wild-type Delta 9*/33 (deletion of exon 9* and inclusion of exon 33) channel was reduced greatly in the scar region and several other isoforms increased. Importantly, a novel 9*/Delta 33 (inclusion of exon 9* and deletion of exon 33) channel was generated in the scar region. Electrophysiological studies showed that the channels found in scar region exhibited hyperpolarized shifts in both the activation and inactivation potentials when expressed in HEK293 cells. The changes of Ca(v)1.2 channels may play a role either in maintenance of muscle excitability and contractility or contribute to arrhythmogenesis.