Creation of a genetic calcium channel blocker by targeted gem gene transfer in the heart
Creation of a genetic calcium channel blocker by targeted gem gene transfer in the heart
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DOI：
10.1161/01.res.0000138449.85324.c5
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发表时间：
2004-08-20
影响因子：
20.1
通讯作者：
Marbán, E
中科院分区：
文献类型：
--
作者：
Murata, M;Cingolani, E;Marbán, E
钙通道阻滞剂是最常用的治疗药物之一。然而，钙通道阻滞剂治疗心脏病的效用是有限的，因为它有强大的血管扩张作用，导致低血压，以及其他可归因于阻断非心脏通道的副作用。因此，通过基因转移来阻断局部钙通道是非常可取的。为了创造局部适用的遗传钙通道阻滞剂，我们通过体细胞基因转移在心脏中过表达了ras相关的小G蛋白Gem。腺病毒载体介导的GEM显著降低心肌细胞L型钙电流密度，使动作电位时程缩短。此外，Gem基因转导后，QT间期明显缩短，左心收缩功能减退。房室结局部注射Gem可显著减慢房室结传导速度(PR间期和AH间期延长)，从而有效地减慢房颤时的心率。这些结果表明，Gem的基因转移具有遗传钙通道阻滞剂的作用，局部应用可以有效地调节心脏的电和收缩功能。
Calcium channel blockers are among the most commonly used therapeutic drugs. Nevertheless, the utility of calcium channel blockers for heart disease is limited because of the potent vasodilatory effect that causes hypotension, and other side effects attributable to blockade of noncardiac channels. Therefore, focal calcium channel blockade by gene transfer is highly desirable. With a view to creating a focally applicable genetic calcium channel blocker, we overexpressed the ras-related small G-protein Gem in the heart by somatic gene transfer. Adenovirus-mediated delivery of Gem markedly decreased L-type calcium current density in ventricular myocytes, resulting in the abbreviation of action potential duration. Furthermore, transduction of Gem resulted in a significant shortening of the electrocardiographic QTc interval and reduction of left ventricular systolic function. Focal delivery of Gem to the atrioventricular (AV) node significantly slowed AV nodal conduction (prolongation of PR and AH intervals), which was effective in the reduction of heart rate during atrial fibrillation. Thus, these results indicate that gene transfer of Gem functions as a genetic calcium channel blocker, the local application of which can effectively modulate cardiac electrical and contractile function.