Expression and function of a biological pacemaker in canine heart.
BACKGROUND
We hypothesized that localized overexpression of the hyperpolarization-activated, cyclic nucleotide-gated (HCN2) pacemaker current isoform in canine left atrium (LA) would constitute a novel biological pacemaker.


RESULTS
Adenoviral constructs of mouse HCN2 and green fluorescent protein (GFP) or GFP alone were injected into LA, terminal studies performed 3 to 4 days later, hearts removed, and myocytes examined for native and expressed pacemaker current (I(f)). Spontaneous LA rhythms occurred after vagal stimulation-induced sinus arrest in 4 of 4 HCN2+GFP dogs and 0 of 3 GFP dogs (P<0.05). Native I(f) in nonexpressed atrial myocytes was 7+/-4 pA at -130 mV (n=5), whereas HCN2+GFP LA had expressed pacemaker current (I(HCN2)) of 3823+/-713 pA at -125 mV (n=10) and 768+/-365 pA at -85 mV.


CONCLUSIONS
HCN2 overexpression provides an I(f)-based pacemaker sufficient to drive the heart when injected into a localized region of atrium, offering a promising gene therapy for pacemaker disease.
Qu
Jihong
J
Department of Pharmacology, Center for Molecular Therapeutics, College of Physicians & Surgeons of Columbia University, New York, NY 10032, USA.
Plotnikov
Alexei N
AN
Danilo
Peter
P
Shlapakova
Iryna
I
Cohen
Ira S
IS
Robinson
Richard B
RB
Rosen
Michael R
MR
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D016275:Atrial Function; D001683:Biological Clocks; D002478:Cells, Cultured; D004285:Dogs; D004553:Electric Conductivity; D004562:Electrocardiography; D005260:Female; D005822:Genetic Vectors; D006325:Heart Atria / Q000378:metabolism*; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D008297:Male; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D015221:Potassium Channels
C578711:Hcn2 protein, mouse; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels; D009124:Muscle Proteins; D015221:Potassium Channels