Creation of a Genetic Calcium Channel Blocker by Targeted Gem Gene Transfer in the Heart

• Published in: Circulation Research 2004-08, Vol.95 (4), p.398-405
• Main Authors: Murata, Mitsushige, Cingolani, Eugenio, McDonald, Amy D, Donahue, J Kevin, Marbán, Eduardo
• Format: Article
• Language: English
• Subjects: Action Potentials - physiology; Adenoviridae - genetics; Animals; Atrial Fibrillation - physiopathology; Atrial Fibrillation - therapy; Atrioventricular Node - physiology; Biological and medical sciences; Calcium Channel Blockers - pharmacology; Calcium Channels, L-Type - physiology; Calcium Signaling - drug effects; Electrocardiography; Fundamental and applied biological sciences. Psychology; Genetic Therapy; Genetic Vectors - administration & dosage; Genetic Vectors - pharmacology; Genetic Vectors - therapeutic use; Guanosine Triphosphate - physiology; Guinea Pigs; Heart Conduction System - physiology; Heart Ventricles - cytology; Immediate-Early Proteins - genetics; Immediate-Early Proteins - physiology; Injections; Ion Channel Gating - physiology; Monomeric GTP-Binding Proteins - genetics; Monomeric GTP-Binding Proteins - physiology; Mutagenesis, Site-Directed; Mutation, Missense; Protein Subunits; Protein Transport; Recombinant Fusion Proteins - physiology; Sus scrofa; Vertebrates: cardiovascular system
• ISSN: 0009-7330; 1524-4571; 1524-4539
• DOI: 10.1161/01.RES.0000138449.85324.c5

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.