Icaritin Inhibits Collagen Degradation-Related Factors and Facilitates Collagen Accumulation in Atherosclerotic Lesions: A Potential Action for Plaque Stabilization.

Zong-Kang Zhang,Bao-Ting Zhang,Jie Li,De-Xin Yan,Wing-Nang Leung

doi:10.3390/ijms17020169

Abstract

Most acute coronary syndromes result from rupture of vulnerable atherosclerotic plaques. The collagen content of plaques may critically affect plaque stability. This study tested whether Icaritin (ICT), an intestinal metabolite of Epimedium-derived flavonoids, could alter the collagen synthesis/degradation balance in atherosclerotic lesions. Rabbits were fed with an atherogenic diet for four months. Oral administration of ICT (10 mg·kg−1·day−1) was started after two months of an atherogenic diet and lasted for two months. The collagen degradation-related parameters, including macrophages accumulation, content and activity of interstitial collagenase-1 (MMP-1), and the collagen synthesis-related parameters, including amount and distribution of smooth muscle cells (SMC) and collagen mRNA/protein levels, were evaluated in the aorta. ICT reduced plasma lipid levels, inhibited macrophage accumulation, lowered MMP-1 mRNA and protein expression, and suppressed proteolytic activity of pro-MMP-1 and MMP-1 in the aorta. ICT changed the distribution of the SMCs towards the fibrous cap of lesions without increasing the amount of SMCs. Higher collagen protein content in lesions and aorta homogenates was observed with ICT treatment compared with the atherogenic diet only, without altered collagen mRNA level. These results suggest that ICT could inhibit the collagen degradation-related factors and facilitate collagen accumulation in atherosclerotic lesions, indicating a new potential of ICT in atherosclerotic plaques.

Highlights

Disruption of atherosclerotic plaques triggers thrombus formation and consequent acute coronary syndromes including unstable angina, acute myocardial infarction, and sudden death [1]
New Zealand White rabbits were randomly assigned to the control, high cholesterol diet (HC), or high cholesterol diet plus ICT administration (HC+ICT) group
After two months of an atherogenic diet, plasma total cholesterol (TC) (HC: 5.91 ̆ 0.44, HC+ICT: 6.36 ̆ 0.37 mmol/L), TG (HC: 2.18 ̆ 0.05, HC+ICT: 1.92 ̆ 0.27 mmol/L) and low-density lipoprotein cholesterol (LDL-C) (HC: 2.81 ̆ 0.06, HC+ICT: 3.00 ̆ 0.21 mmol/L) levels were significantly elevated compared with the control group (TC: 2.27 ̆ 0.22, TG: 0.71 ̆ 0.08, LDL-C: 1.16 ̆ 0.14; p < 0.05 for all 3 markers)

Summary

Introduction

Disruption of atherosclerotic plaques triggers thrombus formation and consequent acute coronary syndromes including unstable angina, acute myocardial infarction, and sudden death [1]. It is well established that a large lipid-rich core underlying a thin fibrous cap containing few smooth muscle cells (SMCs) and collagen content predispose the plaques to rupture [2,3]. Pathological and angiographic studies have determined that the ruptured thin fibrous cap of a coronary atheroma causes acute fatal thrombus formation [4,5]. The SMCs secrete extracellular matrix molecules, including collagen, elastin, and proteoglycans, to form the fibrous cap [1]. Interstitial forms of collagen providing biomechanical strength to the fibrous cap usually protects thrombogenic material in the plaque’s core from contact with coagulation factors in blood [6].

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