Suppression of cell proliferation by tissue plasminogen activator during the early phase after balloon injury minimizes intimal hyperplasia in hypercholesterolemic rabbits.
Thrombus formation is a key component of the pathogenesis of restenosis after arterial balloon injury. The purpose of this study was to determine whether intimal hyperplasia could be attenuated by infusion of recombinant tissue plasminogen activator (tPA). Forty-two Kurosawa and Kusanagi hypercholesterolemic rabbits were divided into tPA (n = 20) and control (n = 22) groups, the former receiving 7 days of continuous tPA infusion (0.6 mg/kg/day) via ear veins. The walls of the common iliac arteries were injured using 2.5-mm balloon catheters and then examined histologically 7, 14, 21, and 28 days later. Cell proliferation was assessed by immunohistochemical analysis of proliferating cell nuclear antigen (PCNA), and transforming growth factor (TGF)-beta immunohistochemistry was carried out to estimate cell proliferation and differentiation. It was observed that 28 days after balloon injury, intimal cross-sectional areas in the tPA group were significantly smaller than in controls (0.11 +/- 0.03 mm2 vs. 0.57 +/- 0.08 mm2, p < 0.01), as were ratios of the cross-sectional areas of the intima and media (0.21 +/- 0.07 vs. 1.06 +/- 0.18, p < 0.05). In addition, the numbers of PCNA-positive medial cells were significantly lower (0.06 +/- 0.01 vs. 0.36 +/- 0.08, p < 0.05) and TGF-beta-positive vessel wall areas were significantly smaller in tPA-treated animals 7 days after balloon injury (0.47 +/- 0.28% vs. 4.55 +/- 1.44%, p < 0.05). Thus infusion of tPA after arterial balloon injury appears to decrease medial cell proliferation and suppress intimal hyperplasia.
Kanamasa
K
K
First Department of Internal Medicine, Kinki University School of Medicine, Osaka, Japan. kanamasa@med.kindai.ac.jp
Otani
N
N
Ishida
N
N
Inoue
Y
Y
Ikeda
A
A
Morii
H
H
Naito
N
N
Hayashi
T
T
Ishikawa
K
K
Miyazawa
M
M
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000473:pathology; D006965:Hyperplasia; D007150:Immunohistochemistry; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000473:pathology; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D011817:Rabbits; D011994:Recombinant Proteins / Q000494:pharmacology; D010959:Tissue Plasminogen Activator / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000032:analysis
D017395:Plasminogen Activator Inhibitor 1; D018809:Proliferating Cell Nuclear Antigen; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D010959:Tissue Plasminogen Activator