Submitted on December 13, 2005
Accepted on July 5, 2006
The up-regulation of proteinase-activated receptors and the hyper-contractile responses precede the development of arterial lesions after balloon injury
Fukunaga Ryota1, Hirano Katsuya1, Hirano Mayumi1, Niiro Naohisa1, Nishimura Junji1, Maehara Yoshihiko2, and Kanaide Hideo3*
1 Division of Molecular Cardiology, Research Institute of Angiocardiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
2 Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Kyushu University COE Program on Lifestyle-Related Diseases, Kyushu University, Fukuoka, Japan
3 Division of Molecular Cardiology, Research Institute of Angiocardiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Kyushu University COE Program on Lifestyle-Related Diseases, Kyushu University, Fukuoka, Japan
* To whom correspondence should be addressed. E-mail: kanaide{at}molcar.med.kyushu-u.ac.jp.
Thrombin and other proteinases exert vascular effects by activating proteinase-activated receptor, PAR. The expression of PAR has been shown to be up-regulated after balloon injury and in human arteriosclerosis. However, the relationship between the receptor up-regulation and the alteration of vasomotor function remains to be elucidated. We herein demonstrated that the contractile responses to PAR-1 and PAR-2 agonist were markedly enhanced in the rabbit femoral arteries after balloon injury. Neointimal thickening was established 4 weeks after the injury. No histological change was observed in the sham operation, where the saphenous artery was ligated without any balloon injury. The contractile response to K+-depolarization was significantly attenuated 1 week after the injury, and then it partly recovered after 4 weeks. Thrombin, PAR-1-activating peptide, trypsin and PAR-2-activating peptide induced no significant contraction in the control. All these stimulants induced enhanced responses 1 week after balloon injury. Such enhanced responses were seen 4 weeks after the injury, except for thrombin. There was no change in the Ca2+-sensitivity of the contractile apparatus, as evaluated in the permeabilized preparations. PAR-1-activating peptide (100 µmol/L), but no other stimulants, induced an enhanced contraction in the sham operation. The expression of PAR-1 and PAR-2 slightly increased after the sham operation, while it markedly and significantly increased after balloon injury. Our observations suggest that balloon injury induced the receptor up-regulation, thereby enhancing the contractile response before the establishment of vascular lesions. The local inflammation associated with the sham operation may also contribute to the receptor up-regulation.
