Rosuvastatin ameliorates the development of pulmonary arterial hypertension in the transgenic (mRen2)27 rat

Vincent G. DeMarco, Javad Habibi, Adam T. Whaley-Connell, Rebecca I. Schneider, James R. Sowers, Bradley T. Andresen, Alex A. Gutweiler, Lixin Ma, Megan S. Johnson, Carlos M. Ferrario, Kevin C. Dellsperger

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21 Scopus citations

Abstract

We have recently reported that transgenic (mRen2)27 rats (Ren2 rats) exhibit pulmonary arterial hypertension (PAH), which is, in part, mediated by oxidative stress. Since 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) exhibit beneficial vascular effects independent of cholesterol synthesis, we hypothesized that rosuvastatin (RSV) treatment ameliorates PAH and pulmonary vascular remodeling in Ren2 rats, in part, by reducing oxidative stress. Six-week-old male Ren2 and Sprague-Dawley rats received RSV (10 mg·kg-1·day-1 ip) or vehicle for 3 wk. After treatment, right ventricular systolic pressure (RVSP) and mean arterial pressure (MAP) were measured. To evaluate treatment effects on pulmonary arteriole remodeling, morphometric analyses were performed to quantitate medial thickening and cell proliferation, whereas whole lung samples were used to quantitate the levels of 3-nitrotyrosine, superoxide, stable nitric oxide (NO) metabolites [nitrates and nitrites (NOx)], and expression of NO synthase isoforms. In the Ren2 rat, RVSP is normal at 5 wk of age, PAH develops between 5 and 7 wk of age, and the elevated pressure is maintained with little variation through 13 wk. At 8 wk of age, left ventricular function and blood gases were normal in the Ren2 rat. Ren2 rats exhibited elevations in medial hypertrophy due to smooth muscle cell proliferation, 3-nitrotyrosine, NO x, NADPH oxidase activity, and endothelial NO synthase expression compared with Sprague-Dawley rats. RSV significantly blunted the increase in RVSP but did not reduce MAP in the Ren2 rat; additionally, RSV significantly attenuated the elevated parameters examined in the Ren2 rat. These data suggest that statins may be a clinically viable adjunct treatment of PAH through reducing peroxynitrite formation.

Original languageEnglish (US)
Pages (from-to)H1128-H1139
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume297
Issue number3
DOIs
Publication statusPublished - Sep 1 2009

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Keywords

  • NADPH oxidase
  • Oxidative stress

ASJC Scopus subject areas

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

Cite this

DeMarco, V. G., Habibi, J., Whaley-Connell, A. T., Schneider, R. I., Sowers, J. R., Andresen, B. T., ... Dellsperger, K. C. (2009). Rosuvastatin ameliorates the development of pulmonary arterial hypertension in the transgenic (mRen2)27 rat. American Journal of Physiology - Heart and Circulatory Physiology, 297(3), H1128-H1139. https://doi.org/10.1152/ajpheart.00048.2009