Attenuation of chronic hypoxic pulmonary hypertension by simvastatin

Reda E. Girgis, Dechun Li, Xinhua Zhan, Joe G.N. Garcia, Rubin M. Tuder, Paul M. Hassoun, Roger A. Johns

Research output: Contribution to journalArticle

Abstract

The 3-hydroxy-methylglutaryl coenzyme A reductase inhibitors (statins) have been shown to improve multiple normal endothelial cell functions and inhibit vascular wall cell proliferation. We hypothesized that one such agent, simvastatin, would attenuate chronic hypoxic pulmonary hypertension. Male adult Sprague-Dawley rats were exposed (14 days) to normoxia (N), normoxia plus once-a-day administered simvastatin (20 mg/kg ip) (NS), hypoxia (10% inspired 02 fraction) (H), or hypoxia plus simvastatin (HS). Mean pulmonary artery pressure, measured in anesthetized, ventilated rats with an open-chest method, was reduced from 25 ± 2 mmHg in H to 18 ± in HS (P < 0.001) but did not reach normoxic values (12 ± 1 mmHg). Similarly, right ventricular/left ventricular plus interventricular septal weight was reduced from 0.53 ± 0.02 in the H group to 0.36 ± 0.02 in the HS group (P < 0.001). The increased hematocrit in H (0.65 ± 0.02) was prevented by simvastatin treatment (0.51 ± 0.01, P < 0.001). Hematocrit was similar in N versus NS. Alveolar vessel muscularization and medial thickening of vessels 50-200 μM in diameter induced by hypoxia were also significantly attenuated in the HS animals. Lung endothelial nitric oxide synthase (eNOS) protein expression in the HS group was less than H (P < 0.01) but was similar in N versus NS. We conclude that simvastatin treatment potently attenuates chronic hypoxic pulmonary hypertension and polycythemia in rats and inhibits vascular remodeling. Enhancement of lung eNOS expression does not appear to be involved in mediating this effect.

Original languageEnglish (US)
Pages (from-to)H938-H945
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume285
Issue number3 54-3
DOIs
StatePublished - Sep 1 2003

Keywords

  • 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibition
  • Nitric oxide
  • Polycythemia
  • Pulmonary vascular remodeling
  • Small G proteins

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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