Targeting neuronal nitric oxide synthase with gene transfer to modulate cardiac autonomic function.
Microdomains of neuronal nitric oxide synthase (nNOS) are spatially localised within both autonomic neurons innervating the heart and post-junctional myocytes. This review examines the use of gene transfer to investigate the role of nNOS in cardiac autonomic control. Furthermore, it explores techniques that may be used to improve upon gene delivery to the cardiac autonomic nervous system, potentially allowing more specific delivery of genes to the target neurons/myocytes. This may involve modification of the tropism of the adenoviral vector, or the use of alternative viral and non-viral gene delivery mechanisms to minimise potential immune responses in the host. Here we show that adenoviral vectors provide an efficient method of gene delivery to cardiac-neural tissue. Functionally, adenovirus-nNOS can increase cardiac vagal responsiveness by facilitating cholinergic neurotransmission and decrease beta-adrenergic excitability. Whether gene transfer remains the preferred strategy for targeting cardiac autonomic impairment will depend on site-specific promoters eliciting sustained gene expression that results in restoration of physiological function.
Mohan
R M
RM
University Laboratory of Physiology, University of Oxford, Parks Road, Oxford OX1 3PT, UK.
Golding
S
S
Heaton
D A
DA
Danson
E J
EJ
Paterson
D J
DJ
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001341:Autonomic Nervous System / Q000473:pathology*; D001933:Brain Stem / Q000473:pathology; D018014:Gene Transfer Techniques; D006801:Humans; D008954:Models, Biological; D009206:Myocardium / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics* / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I
D009569:Nitric Oxide; C496320:NOS1 protein, human; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I