Expressions of Matrix Metalloproteinase-9 and Tissue Inhibitor of Metalloproteinase-2 with Changes of Interleukin-6 and Interleukin-18 in Atherosclerotic Lesions of Hypercholesterolemic Rabbits / 대한흉부외과학회지

ABSTRACT

BACKGROUND: Atherosclerosis is a chronic inflammatory disease of the arterial wall characterized by progressive accumulation of lipids,cells,and extracellular matrix.Matrix metalloproteinases(MMPs)and tissue inhibitor of metalloproteinases(TIMPs)contribute to vascular matrix remodeling in atherosclerosis,and some cytokines may play role in the synthesis or activation of MMPs or TIMPs. MATERIALS AND METHOD: We produced experimental atherosclerotic plaques in 9 rabbits by atherogenic hypercholesterol diet for 12 weeks,and 10 other rabbits were used as control group with standard laboratory chow.At that time,19 rabbits were sacrificed and aorta,coronary arteries and blood specimens were prepared.The expressions of MMP-9,TIMP-2 and interleukin(IL)-18,and the bioactivity of IL-6 were investigated with H&E stain,immunohistochemical stain,immunoblotting(Western blot analysis),and bioassay. RESULT: Serum cholesterol in the experimental group increased up to 1258 +/-262 mg/dL(control group41 +/-7 mg/dL).All experimental group showed well developed atherosclerotic plaques in aorta and coronary artery.The expression of MMP-9 in aorta and coronary artery of the experimental group showed significant increase than that of the control group by immunohistochemistry.Among the experimental group, complicated lesions with intimal rupture or complete luminal occlusion,demonstrated stronger expression of MMP-9.Interestingly,there was no difference in expression of TIMP-2 between the experimental and the control group.These findings were confirmed by Western blot analysis.The bioassay revealed significant up-regulation of serum bioactivity of IL-6 in the experimental group(4819.60 +/-2021.25 IU/ml)compared to that of IL-6 in the control group(27.20 +/-12.19 IU/ml).IL-18 was expressed in all atherosclerotic plaques, whereas little or no expression was detected in the control group. CONCLUSION: The increased MMP-9 expression along with the unchanged TIMP-2 expression seem to be contributory factors in extracellular matrix degradation in atherosclerosis.Focal overexpression of MMP-9 may promote plaque destabilization and cause complications of atherosclerotic plaques such as thrombosis with/without acute coronary syndrome.Elevation of IL-6 and IL-18 may be more than just markers of atherosclerosis but actual participants in lesion development.Identification of critical regulatory pathway is important to improve the understanding of the cellular and molecular basis of atherosclerosis and may open the way for novel therapeutic strategies.