Regulatable atrial natriuretic peptide gene therapy for hypertension.
Hypertension (HTN) is a disease that begins with dysfunctional renal-sodium excretion and progresses to a syndrome of highly elevated systolic, diastolic, and mean arterial pressures. Inadequacies in the therapy of HTN have led to the investigation of the gene therapy of this disease by using systemic overproduction of vasodilatory peptides, such as atrial natriuretic peptide (ANP). However, gene-therapy approaches to HTN using ANP are limited by the need for long-term ANP gene expression and, most important, control of ANP gene expression. Here, we introduce a helper-dependent adenoviral vector carrying the mifepristone (Mfp)-inducible gene-regulatory system to control in vivo ANP expression. In the BPH/2 mouse model of HTN, Mfp-inducible ANP expression was seen for a period of >120 days after administration of vector. Physiological effects of ANP, including decreased systolic blood pressure, increased urinary cGMP output, and decreases in heart weight as a percentage of body weight were also under the control of Mfp. Given these capabilities, this vector represents a paradigm for the gene therapy of HTN.
Schillinger
Kurt J
KJ
Department of Molecular and Cellular Biology, Section of Cardiovascular Sciences and Cardiology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
Tsai
Sophia Y
SY
Taffet
George E
GE
Reddy
Anilkumar K
AK
Marian
Ali J
AJ
Entman
Mark L
ML
Oka
Kazuhiro
K
Chan
Lawrence
L
O'Malley
Bert W
BW
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics* / Q000378:metabolism; D001794:Blood Pressure / Q000502:physiology; D006152:Cyclic GMP / Q000652:urine; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006321:Heart / Q000503:physiopathology; D006973:Hypertension / Q000235:genetics / Q000628:therapy*; D051379:Mice; D015735:Mifepristone / Q000494:pharmacology; D009929:Organ Size
D015735:Mifepristone; D009320:Atrial Natriuretic Factor; D006152:Cyclic GMP