Epidermal growth factor receptor blockade mediates smooth muscle cell apoptosis and improves survival in rats with pulmonary hypertension.
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 alphavbeta3-integrins and epidermal growth factor receptors (EGFRs). This suggests that blockade of these downstream effectors may also induce regression of PAH.


RESULTS
In this study, we first showed in PA organ culture that MMP inhibition or alphavbeta3-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.


CONCLUSIONS
We propose that selective blockade of EGFR signaling may be a novel strategy to reverse progressive, fatal PAH.
Merklinger
Sandra L
SL
Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
Jones
Peter L
PL
Martinez
Eliana C
EC
Rabinovitch
Marlene
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000401:mortality; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors; D008297:Male; D045726:Metalloproteases / Q000037:antagonists & inhibitors / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects*; D009924:Organ Culture Techniques; D011480:Protease Inhibitors / Q000494:pharmacology; D011799:Quinazolines; D051381:Rats; D017207:Rats, Sprague-Dawley; D020032:Tyrphostins / Q000494:pharmacology* / Q000627:therapeutic use
D004791:Enzyme Inhibitors; D039302:Integrin alphaVbeta3; D011480:Protease Inhibitors; D011799:Quinazolines; D020032:Tyrphostins; C101044:RTKI cpd; D066246:ErbB Receptors; D045726:Metalloproteases