Creation of a genetic calcium channel blocker by targeted gem gene transfer in the heart.
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.
Murata
Mitsushige
M
Institute of Molecular Cardiobiology and Division of Cardiology, Department of Medicine, The Johns Hopkins University, Baltimore, Md 21205, USA.
Cingolani
Eugenio
E
McDonald
Amy D
AD
Donahue
J Kevin
JK
Marbán
Eduardo
E
D000200:Action Potentials / Q000502:physiology; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001281:Atrial Fibrillation / Q000503:physiopathology / Q000628:therapy*; D001283:Atrioventricular Node / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000502:physiology*; D020013:Calcium Signaling / Q000187:drug effects; D004562:Electrocardiography; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006160:Guanosine Triphosphate / Q000502:physiology; D006168:Guinea Pigs; D006329:Heart Conduction System / Q000502:physiology; D006352:Heart Ventricles / Q000166:cytology; D017874:Immediate-Early Proteins / Q000235:genetics / Q000502:physiology*; D007267:Injections; D015640:Ion Channel Gating / Q000502:physiology; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000502:physiology*; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D021122:Protein Subunits; D021381:Protein Transport; D011993:Recombinant Fusion Proteins / Q000502:physiology; D034421:Sus scrofa
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D017874:Immediate-Early Proteins; D021122:Protein Subunits; D011993:Recombinant Fusion Proteins; D006160:Guanosine Triphosphate; C088119:Gem protein, mouse; D020559:Monomeric GTP-Binding Proteins