Involvement of RhoA/Rho kinase signaling in protection against monocrotaline-induced pulmonary hypertension in pneumonectomized rats by dehydroepiandrosterone.
RhoA/Rho kinase (ROCK) signaling plays a key role in the pathogenesis of experimental pulmonary hypertension (PH). Dehydroepiandrosterone (DHEA), a naturally occurring steroid hormone, effectively inhibits chronic hypoxic PH, but the responsible mechanisms are unclear. This study tested whether DHEA was also effective in treating monocrotaline (MCT)-induced PH in left pneumonectomized rats and whether inhibition of RhoA/ROCK signaling was involved in the protective effect of DHEA. Three weeks after MCT injection, pneumonectomized rats developed PH with severe vascular remodeling, including occlusive neointimal lesions in pulmonary arterioles. In lungs from these animals, we detected cleaved (constitutively active) ROCK I as well as increases in activities of RhoA and ROCK and increases in ROCK II protein expression. Chronic DHEA treatment (1%, by food for 3 wk) markedly inhibited the MCT-induced PH (mean pulmonary artery pressures after treatment with 0% and 1% DHEA were 33+/-5 and 16+/-1 mmHg, respectively) and severe pulmonary vascular remodeling in pneumonectomized rats. The MCT-induced changes in RhoA/ROCK-related protein expression were nearly normalized by DHEA. A 3-wk DHEA treatment (1%) started 3 wk after MCT injection completely inhibited the progression of PH (mean pulmonary artery pressures after treatment with 0% and 1% DHEA were 47+/-3 and 30+/-3 mmHg, respectively), and this treatment also resulted in 100% survival in contrast to 30% in DHEA-untreated rats. These results suggest that inhibition of RhoA/ROCK signaling, including the cleavage and constitutive activation of ROCK I, is an important component of the impressive protection of DHEA against MCT-induced PH in pneumonectomized rats.
Homma
Noriyuki
N
Cardiovascular Pulmonary Research Laboratory, University of Colorado at Denver and Health Sciences Center, Denver, Colorado, USA.
Nagaoka
Tetsutaro
T
Karoor
Vijaya
V
Imamura
Masatoshi
M
Taraseviciene-Stewart
Laimute
L
Walker
Lori A
LA
Fagan
Karen A
KA
McMurtry
Ivan F
IF
Oka
Masahiko
M
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003687:Dehydroepiandrosterone / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D016686:Monocrotaline / Q000633:toxicity*; D011013:Pneumonectomy; D011651:Pulmonary Artery / Q000201:enzymology / Q000473:pathology; D051381:Rats; D013997:Time Factors; D054460:rho-Associated Kinases / Q000096:biosynthesis*; D020742:rhoA GTP-Binding Protein / Q000096:biosynthesis*
D000276:Adjuvants, Immunologic; D003687:Dehydroepiandrosterone; D016686:Monocrotaline; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein