MMP-2 and MMP-9 Alteration in Response to Collaring in Rabbits: The Effects of Endothelin Receptor Antagonism

Abstract

Matrix metalloproteinases (MMPs), and, in particular, gelatinases (MMP-2 and MMP-9), have been implicated in vascular cell proliferation and/or migration, contributing to intimal thickening, an essential stage in the development of atherosclerosis and restenosis following balloon angioplasty. Endothelin, a strong chemoatractant and mitogen, has been shown to promote smooth muscle cell proliferation and migration by activating MMPs via endothelin-A (ETA) receptors. The positioning of a soft silicon collar around the left carotid artery in rabbits results in intimal thickening. In this study, we investigate the possible role of gelatinases and the effect of a nonselective ETA/ETB receptor antagonist, TAK-044 (5 mg/kg body weight/day, subcutaneously [sc]), on these enzymes. Our results demonstrated that both MMP-2 and MMP-9 activities increased in response to collaring in placebo group, while treatment with TAK-044 significantly suppressed both gelatinase activities and proMMP-2 levels, and inhibited intimal thickening in collared arteries. These results suggest that either enhanced MMP expression or endothelin receptor antagonism may be involved in the formation of intimal thickening in this model.

Endothelin Receptor-Independent Correlation Between HSP47 and Collagen in Rabbit Model of Early Atherosclerosis

“…16 This study was ap pro ved by the Lo cal Et hics Com mit te e of the Fa culty of Phar macy, Ege Uni ver sity, Iz mir, Tur key. All ani mals re ce i ved care comp li ed with the "Prin cip le of La bo ra tory Ani mal ca re " for mu la ted by the Na ti o nal So ci ety for Me di cal Re se arch and the "Gu i de for Ca re and Use of La bo ra tory Ani mal s" pre pa red by the Ins ti tu te of La bo ra tory Ani mal Re so ur ces.…”

“…Thro ug ho ut the 3-we ek tre at ment pe ri od, the first gro up (n= 10) re ce i ved TAK-044 (5 mg/kg/ day, s.c.). 16,17 The se cond (pla ce bo) gro up (n= 10) re ce i ved only the ve hic le (0.9% NaCl 0.8 ml/kg/ day, s.c.). Each rab bit was kept in a se pa ra te ca ge and al lo wed ac cess to a re gu lar di et (stan dard rabbit chow and tap wa ter ad li bi tum).…”

“…2,16 The con tra la te ral ca ro tid ar tery was shamope ra ted. The ca ro tid ar te ri es we re then re tur ned to the ir ori gi nal po si ti ons and the in ci si ons su tured.…”

“…16 Then, the seg ments we re im me di a tely pla ced in 10% ne ut ral buf fe red for ma lin for 24 hours, dehy dra ted in a gra ded se ri es of isop ropyl al cohol (60 to 100%) and fol lo wed by xylol be fo re be ing em bed ded in pa raf fin.…”

“…We al so sho wed that a non se lec ti ve en dot he lin recep tor an ta go nist, TAK-044, in hi bi ted in ti mal thicke ning, MMP up re gu la ti on and ac ti va ti on in this mo del. 15,16 Thus, in this study, we ai med to in ves tiga te the pos sib le ro le of HSP47, the re la ti on betwe en HSP47 and col la gen sythe sis, and al so the ef fects of a non se lec ti ve ETA/ETB re cep tor an tago nist, TAK-044 in col lar-in du ced early at he roscle ro sis mo del.…”