Regression of chronic hypoxic pulmonary hypertension by simvastatin

Reda E. Girgis, Shehzin Mozammel, Hunter C. Champion, Dechun Li, Xinqi Peng, Larissa Shimoda, Rubin M. Tuder, Roger A Johns, Paul M Hassoun

Research output: Contribution to journalArticle

Abstract

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% FIO2) 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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume292
Issue number5
DOIs
StatePublished - May 2007

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Simvastatin
Pulmonary Hypertension
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Hydroxymethylglutaryl CoA Reductases
Pulmonary Artery
Myosin-Light-Chain Phosphatase
rho-Associated Kinases
Mevalonic Acid
Myosins
Western Blotting
Phosphorylation
Pressure
Weights and Measures
Lung
Hypoxia

Keywords

  • Mevalonate
  • Rho-kinase
  • Statins

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Cell Biology
  • Physiology

Cite this

Regression of chronic hypoxic pulmonary hypertension by simvastatin. / Girgis, Reda E.; Mozammel, Shehzin; Champion, Hunter C.; Li, Dechun; Peng, Xinqi; Shimoda, Larissa; Tuder, Rubin M.; Johns, Roger A; Hassoun, Paul M.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 292, No. 5, 05.2007.

Research output: Contribution to journalArticle

Girgis, Reda E. ; Mozammel, Shehzin ; Champion, Hunter C. ; Li, Dechun ; Peng, Xinqi ; Shimoda, Larissa ; Tuder, Rubin M. ; Johns, Roger A ; Hassoun, Paul M. / Regression of chronic hypoxic pulmonary hypertension by simvastatin. In: American Journal of Physiology - Lung Cellular and Molecular Physiology. 2007 ; Vol. 292, No. 5.
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abstract = "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{\%} FIO2) 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.",
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AU - Tuder, Rubin M.

AU - Johns, Roger A

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AB - 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% FIO2) 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.

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