Regression of chronic hypoxic pulmonary hypertension by simvastatin.
The 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitor, simvastatin, has been shown to attenuate chronic hypoxic pulmonary hypertension (CHPH). Here, we assess whether simvastatin is capable of inducing regression of established CHPH and explore potential mechanisms of statin effect. Rats (n = 8 in each group) were exposed to chronic hypoxia (10% Fi(O(2))) for 2 or 4 wk. Simvastatin treatment (20 mg.kg(-1).day(-1)) commenced after 2 wk of hypoxia, at which time CHPH was fully established, reduced mean pulmonary artery pressure (19 +/- 0.5 vs. 27 +/- 0.9 mmHg; P < 0.001), the ratio of right ventricular free wall to left ventricular plus septal weight (0.41 +/- 0.03 vs. 0.54 +/- 0.03; P < 0.001), and medial thickening of small pulmonary arteries (13 +/- 0.4 vs. 16 +/- 0.4%; P < 0.01) compared with 4-wk hypoxic controls. Supplementation with mevalonate (50 mg.kg(-1).day(-1)) prevented the attenuation of CHPH induced by simvastatin during 2 wk of hypoxia. Because statins are known to inhibit Rho-kinase (ROCK), we determined expression of ROCK-1 and -2 in whole lung by Western blot and ROCK activity by phosphorylation of the myosin-binding subunit of myosin phosphatase. Expression of both ROCK-1 and -2 were markedly diminished in simvastatin-treated animals during normoxia and hypoxia (2- and 4-wk) exposure (P < 0.01). ROCK activity was increased threefold under hypoxic conditions and normalized with simvastatin treatment (P < 0.001). We conclude that simvastatin attenuates and induces regression of established CHPH through inhibition of HMG-CoA reductase. Inhibition of ROCK expression and activity may be an important mechanism of statin effect.
Girgis
Reda E
RE
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. rgirgis@jhmi.edu
Mozammel
Shehzin
S
Champion
Hunter C
HC
Li
Dechun
D
Peng
Xinqi
X
Shimoda
Larissa
L
Tuder
Rubin M
RM
Johns
Roger A
RA
Hassoun
Paul M
PM
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects / Q000473:pathology; D011652:Pulmonary Circulation; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000627:therapeutic use*; D054460:rho-Associated Kinases
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D019821:Simvastatin; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases