Repeated gene transfer of naked prostacyclin synthase plasmid into skeletal muscles attenuates monocrotaline-induced pulmonary hypertension and prolongs survival in rats.
A safer, less invasive method for repeated transgene administration is desirable for clinical application of gene therapy targeting chronic diseases, including pulmonary hypertension (PH). Thus, effects of prostaglandin I2 (prostacyclin) synthase (PGIS) gene transfer by the naked DNA method into skeletal muscle were investigated in monocrotaline (MCT)-induced PH rats. A single injection of rat PGIS cDNA-encoding plasmid into thigh muscle 3 days after bupivacaine pretreatment transiently increased muscle PGIS protein expression and muscle and serum levels of a stable prostacyclin metabolite (6-keto-prostaglandin F1). The muscle 6-keto-prostaglandin F1 level peaked on day 2 but was still elevated on day 7; prostacyclin selectively increased lung cyclic AMP levels as compared with liver and kidney. MCT induced a marked rise in right ventricular (RV) systolic pressure, pulmonary arterial wall thickening, and RV hypertrophy. Repeated PGIS gene transfer every week lowered RV systolic pressure and ameliorated RV and pulmonary artery remodeling in MCT-induced PH rats. Furthermore, repeated PGIS gene transfer significantly improved the survival rate of MCT-induced PH rats. In conclusion, repeated PGIS gene transfer into skeletal muscle not only attenuated the development of PH and cardiovascular remodeling but also improved the prognosis for MCT-induced PH rats. This study may provide insight into a new treatment strategy for PH.
Tahara
Nobuhiro
N
Third Department of Internal Medicine and Cardiovascular Research Institute, Kurume University School of Medicine, Kurume 830-0011, Japan.
Kai
Hisashi
H
Niiyama
Hiroshi
H
Mori
Takahiro
T
Sugi
Yusuke
Y
Takayama
Narimasa
N
Yasukawa
Hideo
H
Numaguchi
Yasushi
Y
Matsui
Hideo
H
Okumura
Kenji
K
Imaizumi
Tsutomu
T
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D000242:Cyclic AMP / Q000032:analysis / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000008:administration & dosage* / Q000235:genetics; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000378:metabolism / Q000628:therapy*; D017380:Hypertrophy, Right Ventricular / Q000473:pathology / Q000503:physiopathology; D019746:Intramolecular Oxidoreductases / Q000008:administration & dosage* / Q000235:genetics; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016686:Monocrotaline; D018482:Muscle, Skeletal / Q000378:metabolism*; D010957:Plasmids; D011379:Prognosis; D011651:Pulmonary Artery / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D015996:Survival Rate; D013997:Time Factors
D015121:6-Ketoprostaglandin F1 alpha; D016686:Monocrotaline; D003577:Cytochrome P-450 Enzyme System; D000242:Cyclic AMP; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase