Longitudinal transcriptional analysis of developing neointimal vascular occlusion and pulmonary hypertension in rats.
Pneumonectomized rats injected with the alkaloid toxin, monocrotaline, develop progressive neointimal pulmonary vascular obliteration and pulmonary hypertension resulting in right ventricular failure and death. The antiproliferative immunosuppressant, triptolide, attenuates neointimal formation and pulmonary hypertension in this disease model (Faul JL, Nishimura T, Berry GJ, Benson GV, Pearl RG, and Kao PN. Am J Respir Crit Care Med 162: 2252-2258, 2000). Pneumonectomized rats, injected with monocrotaline on day 7, were killed at days 14, 21, 28, and 35 for measurements of physiology and gene expression patterns. These data were compared with pneumonectomized, monocrotaline-injected animals that received triptolide from day 5 to day 35. The hypothesis was tested that a group of functionally related genes would be significantly coexpressed during the development of disease and downregulated in response to treatment. Transcriptional analysis using total lung RNA was performed on replicate animals for each experimental time point with exploratory data analysis followed by statistical significance analysis. Marked, statistically significant increases in proteases (particularly derived from mast cells) were noted that parallel the development of vascular obliteration and pulmonary hypertension. Mast-cell-derived proteases may play a role in regulating the development of neointimal pulmonary vascular occlusion and pulmonary hypertension in response to injury.
Vaszar
Laszlo T
LT
Division of Pulmonary/Critical Care Medicine, Stanford University Medical Center, Stanford, California 94305-5236, USA.
Nishimura
Toshihiko
T
Storey
John D
JD
Zhao
Guohua
G
Qiu
Daoming
D
Faul
John L
JL
Pearl
Ronald G
RG
Kao
Peter N
PN
D000818:Animals; D001157:Arterial Occlusive Diseases / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D015152:Blotting, Northern; D016000:Cluster Analysis; D004224:Diterpenes / Q000627:therapeutic use; D004852:Epoxy Compounds; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006439:Hemodynamics; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D008137:Longitudinal Studies; D008297:Male; D016686:Monocrotaline; D010616:Phenanthrenes / Q000627:therapeutic use; D011013:Pneumonectomy; D011651:Pulmonary Artery / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014158:Transcription, Genetic; D017539:Tunica Intima / Q000473:pathology
D004224:Diterpenes; D004852:Epoxy Compounds; D010616:Phenanthrenes; D012333:RNA, Messenger; C001899:triptolide; D016686:Monocrotaline