Faculty Collaboration Database

Targeted nonviral gene-based inhibition of Gα(i/o)-mediated vagal signaling in the posterior left atrium decreases vagal-induced atrial fibrillation. Heart Rhythm 2011 Nov;8(11):1722-9

Date

06/22/2011

Pubmed ID

21689540

Pubmed Central ID

PMC3570566

DOI

10.1016/j.hrthm.2011.06.018

Scopus ID

2-s2.0-80055024244 (requires institutional sign-in at Scopus site)   37 Citations

Abstract

BACKGROUND: Pharmacologic and ablative therapies for atrial fibrillation (AF) have suboptimal efficacy. Newer gene-based approaches that target specific mechanisms underlying AF are likely to be more efficacious in treating AF. Parasympathetic signaling appears to be an important contributor to AF substrate.

OBJECTIVE: The purpose of this study was to develop a nonviral gene-based strategy to selectively inhibit vagal signaling in the left atrium and thereby suppress vagal-induced AF.

METHODS: In eight dogs, plasmid DNA vectors (minigenes) expressing Gα(i) C-terminal peptide (Gα(i)ctp) was injected in the posterior left atrium either alone or in combination with minigene expressing Gα(o)ctp, followed by electroporation. In five control dogs, minigene expressing scrambled peptide (Gα(R)ctp) was injected. Vagal- and carbachol-induced left atrial effective refractory periods (ERPs), AF inducibility, and Gα(i/o)ctp expression were assessed 3 days following minigene delivery.

RESULTS: Vagal stimulation- and carbachol-induced effective refractory period shortening and AF inducibility were significantly attenuated in atria receiving a Gα(i2)ctp-expressing minigene and were nearly eliminated in atria receiving both Gα(i2)ctp- and Gα(o1)ctp-expressing minigenes.

CONCLUSION: Inhibition of both G(i) and G(o) proteins is necessary to abrogate vagal-induced AF in the left atrium and can be achieved via constitutive expression of Gα(i/o)ctps expressed by nonviral plasmid vectors delivered to the posterior left atrium.

Author List

Aistrup GL, Cokic I, Ng J, Gordon D, Koduri H, Browne S, Arapi D, Segon Y, Goldstein J, Angulo A, Wasserstrom JA, Goldberger JJ, Kadish AH, Arora R

MESH terms used to index this publication - Major topics in bold

Animals
Atrial Fibrillation
Carbachol
Cholinergic Agonists
DNA
Dogs
GTP-Binding Protein alpha Subunits
Gene Expression
Genetic Therapy
Genetic Vectors
Heart Atria
Vagus Nerve