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1 Internal Medicine, Johns Hopkins University, Baltimore, Maryland, United States
2 Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
3 Internal Medicine, Johns Hopkins University, Baltimore, Maryland, United States; Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
* To whom correspondence should be addressed. E-mail: rgirgis{at}jhmi.edu.
The 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% FiO2) for 2 or 4 wks. Simvastatin treatment (20 mg/kg/d) commenced after 2 wks of hypoxia, at which time CHPH was fully established, reduced mean pulmonary artery pressure (PAP; 19 ±0.5 vs. 27 ± 0.9 mmHg, P<0.001), the ratio of right ventricular free wall to left ventricular plus septal weight (RV/LV+S; 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/d) prevented the attenuation of CHPH induced by simvastatin during 2 wks 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 Rho-kinase 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 3-fold 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 Rho-kinase expression and activity may be an important mechanism of statin effect.
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