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(Hypertension. 2000;36:364.)
© 2000 American Heart Association, Inc.

Scientific Contributions

Bradykinin B₁ Receptor Mediates Inhibition of Neointima Formation in Rat Artery After Balloon Angioplasty

Jun Agata; Robert Q. Miao; Katsutoshi Yayama; Lee Chao; Julie Chao

From the Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston.

Correspondence to Julie Chao, PhD, Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425-2211. E-mail chaoj{at}musc.edu

Abstract—We evaluated the effects of the kallikrein-kinin system on the proliferation and migration of primary cultured vascular smooth muscle cells (VSMCs) in vitro and neointima formation in balloon-injured rat carotid arteries in vivo. In cultured rat VSMCs, tissue kallikrein inhibited cell proliferation, and this inhibitory effect was blocked by Sar-Tyr-Aca()-Lys [D-ßNal⁷,Ile⁸]-des-Arg⁹-bradykinin, a bradykinin B₁ receptor antagonist, and by icatibant, a bradykinin B₂ receptor antagonist. Platelet-derived growth factor significantly increased the expression of the B₁ receptor but not the B₂ receptor in VSMCs. Platelet-derived growth factor–induced cell migration was significantly attenuated by des-Arg⁹-bradykinin and to a lesser degree by bradykinin. Endogenous B₁ receptor mRNA increased in rat carotid arteries after balloon angioplasty. After local delivery of adenovirus carrying the human tissue kallikrein gene into the rat carotid artery, we observed a 54% reduction in the intima/media ratio at the injured site compared with the control ratio (n=7, P<0.01). Administration of the B₁ receptor antagonist via minipumps blocked the protective effect of kallikrein and partially reversed the intima/media ratio toward the control ratio. Kallikrein gene delivery results in the regeneration of endothelium compared with the control groups, and the B₁ receptor antagonist abolished this effect. Nitrite/nitrate, cGMP, and cAMP levels in balloon-injured arteries significantly increased after kallikrein gene delivery, whereas the B₁ receptor antagonist abolished these increases (n=4 or 5, P<0.05). These results indicate that the B₁ receptor contributes to the reduction of neointima formation via the promotion of reendothelialization and inhibition of VSMC proliferation and migration through NO-cGMP and cAMP signaling pathways. This study provides significant implications in treating restenosis after revascularization.

Key Words: bradykinin • kallikrein-kinin system • gene delivery • cell migration • neointima formation

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