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1 Medicine, University of Colorado Health Sciences Center, Denver, Colorado, United States
2 Pathology, University of Colorado Health Sciences Center, Denver, Colorado, United States
3 Pathology, Johns Hopkins University, Baltimore, Maryland, United States
4 Medicine, University of Colorado Health Sciences Center,, Denver, Colorado, United States
5 Anatomy, Technical University Dresden, Dresden, Germany
* To whom correspondence should be addressed. E-mail: norbert.voelkel{at}uchsc.edu.
Severe pulmonary hypertension (SPH) is characterized by precapillary arteriolar lumen obliteration, dramatic right ventricular hypertrophy and pericardial effusion. Our recently published rat model of SPH recapitulates major components of the human disease. We used this model to develop new treatment strategies for SPH. SPH in rats was induced using vascular endothelial growth factor (VEGF) receptor blockade in combination with chronic hypoxia. A large variety of drugs used in this study, including anticancer drugs -- cyclophosphamide and paclitaxel - the ACE inhibitor lisinopril, the anti-angiogenic agent thalidomide, and the PPAR
agonist PGJ2, failed to decrease mean pulmonary artery pressure (PAP) or right ventricular hypertrophy. In contrast, treatment of rats with established SPH with simvastatin markedly reduced mean PAP and right ventricular hypertrophy and this reduction was associated with caspase-3 activation and pulmonary microvascular endothelial cell apoptosis. Simvastatin partially restored caveolin-1-, caveolin-2- and phospho-caveolin expression in the vessel walls. In rat primary pulmonary microvascular endothelial cells (RPMVEC) simvastatin induced caspase 3 activation and Rac 1 expression while suppressing Rho A, and attenuated levels of Akt and Erk phosphorylation. We conclude that simvastatin is effective in inducing apoptosis in hyperproliferative pulmonary vascular lesions and could be considered as a potential drug for treatment of human SPH.
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