Rapamycin attenuates hypoxia-induced pulmonary vascular remodeling and right ventricular hypertrophy in mice.
BACKGROUND
Chronic hypoxia induces pulmonary arterial hypertension (PAH). Smooth muscle cell (SMC) proliferation and hypertrophy are important contributors to the remodeling that occurs in chronic hypoxic pulmonary vasculature. We hypothesized that rapamycin (RAPA), a potent cell cycle inhibitor, prevents pulmonary hypertension in chronic hypoxic mice.


METHODS
Mice were held either at normoxia (N; 21% O2) or at hypobaric hypoxia (H; 0.5 atm; ~10% O2). RAPA-treated animals (3 mg/kg*d, i.p.) were compared to animals injected with vehicle alone. Proliferative activity within the pulmonary arteries was quantified by staining for Ki67 (positive nuclei/vessel) and media area was quantified by computer-aided planimetry after immune-labeling for alpha-smooth muscle actin (pixel/vessel). The ratio of right ventricle to left ventricle plus septum (RV/[LV+S]) was used to determine right ventricular hypertrophy.


RESULTS
Proliferative activity increased by 34% at day 4 in mice held under H (median: 0.38) compared to N (median: 0.28, p = 0.028) which was completely blocked by RAPA (median HO+RAPA: 0.23, p = 0.003). H-induced proliferation had leveled off within 3 weeks. At this time point media area had, however, increased by 53% from 91 (N) to 139 (H, p < 0.001) which was prevented by RAPA (H+RAPA: 102; p < 0.001). RV/[LV+S] ratio which had risen from 0.17 (N) to 0.26 (H, p < 0.001) was attenuated in the H+RAPA group (0.22, p = 0.041). For a therapeutic approach animals were exposed to H for 21 days followed by 21 days in H +/- RAPA. Forty two days of H resulted in a media area of 129 (N: 83) which was significantly attenuated in RAPA-treated mice (H+RAPA: 92). RV/[LV+S] ratios supported prevention of PH (N 0.13; H 0.27; H+RAPA 0.17). RAPA treatment of N mice did not influence any parameter examined.


CONCLUSIONS
Therapy with rapamycin may represent a new strategy for the treatment of pulmonary hypertension.
Paddenberg
Renate
R
Institute of Anatomy and Cell Biology, Giessen University, Giessen, Germany. Renate.Paddenberg@anatomie.med.uni-giessen.de
Stieger
Philipp
P
von Lilien
Anna-Laura
AL
Faulhammer
Petra
P
Goldenberg
Anna
A
Tillmanns
Harald H
HH
Kummer
Wolfgang
W
Braun-Dullaeus
Ruediger C
RC
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D017380:Hypertrophy, Right Ventricular / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D000860:Hypoxia / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D008168:Lung / Q000098:blood supply* / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use*
D020123:Sirolimus