Gene transfer of endothelial nitric oxide synthase attenuates flow-induced pulmonary hypertension in rabbits.
BACKGROUND
Nitric oxide, a potent vasodilator with an important role in the regulation of pulmonary vascular tone, is synthesized by a family of nitric oxide synthases. To determine whether endothelial nitric oxide synthase (eNOS) gene transfer may prevent pulmonary hypertension, the effects of transfer of the eNOS gene to the lung were studied in rabbits with pulmonary hypertension induced by high pulmonary blood flow.


METHODS
Adenoviral vector encoding the eNOS gene was intratracheally transfected into the lung of rabbits with flow-induced pulmonary hypertension. Rabbits instilled intratracheally with adenoviral vector without encoding the eNOS gene served as a control group. Hemodynamic data were recorded before and after transfection, and transgene expression was investigated.


RESULTS
Pulmonary hypertension was significantly attenuated in eNOS gene-transfected rabbits compared with control animals (mean pulmonary arterial pressure, 22.3 +/- 5.5 versus 41.0 +/- 6.9 mm Hg; pulmonary vascular resistance, 326 +/- 42 versus 618 +/- 66 dynes x s x cm(-5); p < 0.01). Systemic arterial pressure and systemic vascular resistance were unaffected. There was an increase in calcium-dependent conversion of L-arginine to L-citrulline in the lung (16.81 +/- 0.72 versus 4.11 +/- 0.41 pmol x mg protein(-1) x h(-1)) and cyclic guanosine monophosphate levels (0.138 +/- 0.015 versus 0.065 +/- 0.003 pmol/mg protein). Immunohistochemical staining showed expression of the eNOS gene was detected mainly in endothelial cells of small pulmonary vessels. Transgene expression was confirmed using Western blot analysis.


CONCLUSIONS
These data suggest that intratracheal adenoviral-mediated eNOS gene transfer can attenuate flow-induced pulmonary hypertension in rabbits and may represent a new form of therapy for the treatment of flow-induced pulmonary hypertension.
Zhang
Fengwei
F
Department of Cardiovascular Surgery, Qilu Hospital of Shandong University, Jinan, Shandong Province, China. zfwei@126.com
Wu
Shuming
S
Lu
Xianshuo
X
Wang
Mo
M
Liu
Meiming
M
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D015153:Blotting, Western; D006152:Cyclic GMP / Q000378:metabolism; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D006439:Hemodynamics / Q000502:physiology; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D007150:Immunohistochemistry; D008297:Male; D019001:Nitric Oxide Synthase / Q000235:genetics* / Q000378:metabolism; D011336:Probability; D011652:Pulmonary Circulation / Q000502:physiology*; D011817:Rabbits; D011897:Random Allocation; D012016:Reference Values; D012680:Sensitivity and Specificity; D014162:Transfection
D019001:Nitric Oxide Synthase; D006152:Cyclic GMP