doi: 10.1161/CIRCULATIONAHA.105.540542
(Circulation. 2005;112:423-431.)
© 2005 American Heart Association, Inc.
Vascular Medicine |
Epidermal Growth Factor Receptor Blockade Mediates Smooth Muscle Cell Apoptosis and Improves Survival in Rats With Pulmonary Hypertension
From the Department of Pediatrics (S.L.M., E.C.M., M.R.), Stanford University School of Medicine, Stanford, Calif, and University of Colorado Health Sciences Center (P.L.J.), Denver.
Correspondence to Marlene Rabinovitch, Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford University School of Medicine, CCSR Bldg, Room 2245b, 269 Campus Dr, Stanford, CA 94305-5162. E-mail marlener{at}stanford.edu
Received February 2, 2005; revision received April 7, 2005; accepted April 11, 2005.
Background— We previously reported that administration of elastase inhibitors reverses fatal pulmonary arterial hypertension (PAH) in rats by inducing smooth muscle cell (SMC) apoptosis. We showed in pulmonary artery (PA) organ culture that the mechanism by which elastase inhibitors induce SMC apoptosis involves repression of matrix metalloproteinase (MMP) activity and subsequent signaling through 
vß3-integrins and epidermal growth factor receptors (EGFRs). This suggests that blockade of these downstream effectors may also induce regression of PAH.
Methods and Results— In this study, we first showed in PA organ culture that MMP inhibition or vß3-integrin blockade with agents in clinical and preclinical use (SC-080 and cilengitide, respectively) mediates SMC apoptosis and regression of medial hypertrophy. We also documented similar results with an EGFR tyrosine kinase inhibitor. We then induced PAH in rats by injection of monocrotaline and, at day 21, began a 2-week treatment with SC-080, cilengitide, or the EGFR inhibitor PKI166. No vehicle- or cilengitide-treated animal survived beyond 2 weeks. Administration of SC-080 resulted in 44% survival at 2 weeks, and PKI166 therapy resulted in 78% and 54% survival in daily or 3-times-weekly treated animals, respectively. Four weeks after cessation of PKI166, we documented survivals of 50% and 23% in the 2 treatment groups, associated with reductions in pulmonary pressure, right ventricular hypertrophy, and abnormally muscularized distal arteries.
Conclusion— We propose that selective blockade of EGFR signaling may be a novel strategy to reverse progressive, fatal PAH.
Key Words: cells • pulmonary heart disease • integrins • metalloproteinases • hypertension, pulmonary
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