Role of endothelial nitric oxide synthase and collagen metabolism in right ventricular remodeling due to pulmonary hypertension.
BACKGROUND
Pulmonary hypertension (PH) causes elevated right ventricular (RV) systolic pressure, RV remodeling and finally RV failure to death. However, the mechanisms of RV remodeling in PH remain to be fully elucidated.


RESULTS
RV autopsy samples from 6 PH patients with RV failure against 3 age- and sex-matched controls were first examined. Next, RV remodeling in 2 mouse models of chronic hypoxia-induced PH with endothelial nitric oxide synthase-deficient (eNOS(-/-)) and collagenase-resistant knock-in (Col(R/R)) mice were examined. In humans, RV failure was associated with RV hypertrophy, interstitial and perivascular fibrosis, decreased RV capillary density and increased macrophage recruitment. Furthermore, immunostaining showed that perivascular matrix metalloproteinase-2 was increased in PH patients with RV failure. In animals, both hypoxic eNOS(-/-) and Col(R/R) mice developed a greater extent of RV hypertrophy, perivascular remodeling and macrophage infiltration compared with wild-type mice. Capillary rarefaction was developed in hypoxic eNOS(-/-) mice, while Col(R/R) mice were able to increase their capillary density in the RV in response to chronic hypoxia. Both mouse models showed increased autophagy even under normoxic condition.


CONCLUSIONS
These results indicate that RV remodeling occurs early during PH development through fibrosis, perivascular remodeling, capillary rarefaction and autophagy, in which the eNOS pathway and collagen metabolism might be involved.
Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine.
Suvd
S
Nergui
Yoshihiro
Y
Fukumoto
Zhulanqiqige
Z
Do E
Sota
S
Nakajima
Toru
T
Shimizu
Shohei
S
Ikeda
Md
M
Elias-Al-Mamun
Hiroaki
H
Shimokawa
D000328:Adult; D000818:Animals; D001343:Autophagy / Q000235:genetics; D003094:Collagen / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005355:Fibrosis; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D020257:Ventricular Remodeling
D003094:Collagen; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse