Delivery of ion channel genes to treat cardiovascular diseases.
Modifying ion channel expression and function in the heart and vasculature are potentially useful, novel approaches to managing cardiac hypertrophy, atrial fibrillation and hypertension. Calcium channels play a pivotal role in the heart and vasculature in controlling muscle contraction as well as other aspects of calcium-dependent signaling. The present investigation reports development of mutated L-type calcium channel beta subunits that are delivered by an adenoviral vector to vascular smooth muscle tissue. Wild type subunits serve a chaperone function for the pore-forming alpha(1C) subunit of the calcium channel, localize to the cell membrane and enhance calcium current. Conversely, mutated subunits function as dominant negative, defective chaperone molecules that disrupt targeting to the cell membrane and decrease calcium current. The dominant negative genes can be delivered in vitro and ex vivo, and have the potential to decrease arterial tone and lower blood pressure in vivo.
Marsh
James D
JD
Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA. jdmarsh@uams.edu
Telemaque
Sabine
S
Rhee
Sung W
SW
Stimers
Joseph R
JR
Rusch
Nancy J
NJ
D000818:Animals; D020746:Calcium Channels, L-Type / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D002318:Cardiovascular Diseases / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy*; D002478:Cells, Cultured; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology / Q000628:therapy; D007473:Ion Channels / Q000235:genetics* / Q000502:physiology; D008638:Mesenteric Arteries / Q000166:cytology / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000502:physiology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D020746:Calcium Channels, L-Type; D007473:Ion Channels; D011993:Recombinant Fusion Proteins