Monocyte Chemoattractant Protein-1 Is an Essential Inflammatory Mediator in Angiotensin II-Induced Progression of Established Atherosclerosis in Hypercholesterolemic Mice

Abstract

Objective-Chronic inflammatory processes might be involved in the progression and destabilization of atherosclerotic plaques. Therefore, identification of the mechanism underlying arterial inflammatory function might lead to the development of novel therapeutic strategies. Angiotensin II (AngII) is implicated in atherogenesis by activating the vascular inflammation system, mainly through monocyte chemotaxis. Therefore, we hypothesized that AngII increases plaque size and promotes destabilization of established atheromas by activating the monocyte chemoattractant protein-1 (MCP-1) pathway. Methods and Results-We report here that 4-week infusion of AngII not only increased plaque size but also induced a destabilization phenotype (ie, increased macrophages and lipids and decreased collagen and smooth muscle cells) of pre-existing atherosclerotic lesions of hypercholesterolemic mice. AngII also enhanced the gene expression of inflammatory cytokines (TNF␣, etc.) and chemokines CCR2, etc Key Words: atherosclerosis Ⅲ hypercholesterolemia Ⅲ cell adhesion molecules Ⅲ inflammation Ⅲ gene therapy A therosclerosis and its complications are the major cause of death in Western countries. Recent evidence suggests that chronic inflammatory processes have an important role in atherosclerotic plaque progression, destabilization, and subsequent rupture/thrombosis, resulting in acute coronary syndrome and stroke. 1 Therefore, identification of the critical inflammatory pathway involved in plaque progression and destabilization of pre-existing established atheromas might aid in the development of novel therapeutic strategies to reduce atherothrombotic complications. Angiotensin II (AngII) is implicated in atherogenesis beyond its hemodynamic effects. 2 Infusion of AngII into hypercholesterolemic mice dramatically accelerates the development and/or progression of atherosclerotic lesions and the effects of AngII occurred independent of changes in arterial pressure or plasma lipid concentration. 3,4 The mechanism of AngII-induced enhancement of atherogenesis is probably multifactorial, and includes hemodynamic effects, endothelial dysfunction and activation, 5 oxidative stress, 6 and inflammation. 7,8 AngII increases monocyte chemotaxis, activates nuclear factor-B, and augments production of inflammatory cytokines and chemokines by arterial wall cells and monocytes. 9 -12 AngII is very important in the pathogenesis of atherothrombotic complications, as evidenced by clinical benefits of angiotensinconverting enzyme inhibition 13 and AngII receptor blockers. 14 There are no reports, however, that address the mechanism of AngII-induced enhancement of atherogenesis and plaque destabilization under in vivo conditions.Emerging evidence suggests that AngII activates cell inflammatory systems in arterial lesion. 1,2 Inflammatory changes in arterial lesions are characterized by the recruitment and activation of monocytes/macrophages, which are regulated by monocyte chemoattractant protein-1 (MCP-1). 15 Expression Vector7ND was constructed b...

Dietary Cholesterol Oxidation Products Accelerate Plaque Destabilization and Rupture Associated with Monocyte Infiltration/Activation via the MCP-1-CCR2 Pathway in Mouse Brachiocephalic Arteries: Therapeutic Effects of Ezetimibe

“…In a previous study that examined the therapeutic effects of anti-atherosclerotic drugs 17) , an excess of 60 animals was needed per group to ensure that the studies were adequately powered. To overcome this problem, we performed chronic infusion of angiotensin Ⅱ in addition to HFD feeding in ApoE −/− mice because this has been used to enhance the features of atherogenesis, such as monocyte-mediated inflammation, lipid accumulation, and MMP activation 22,24) . We found that chronic angiotensin Ⅱ infusion could increase the incidence of plaque rupture from less than 1 rupture per plaque (authors' unpublished observation) to 3.4 per plaque (Fig.…”

“…After 4 weeks on the experimental diets, all mice received angiotensin Ⅱ (1.9 mg/kg per day) for 4 weeks 22,24) . Angiotensin Ⅱ was dissolved in phosphate-buffered saline and loaded into miniosmotic pumps (Alzet, Cupertino, CA) according to the recommendations of the manufacturer.…”

Matrix Metalloproteinase 2 Activation of Transforming Growth Factor-β1 (TGF-β1) and TGF-β1–Type II Receptor Signaling Within the Aged Arterial Wall

“…23,24 The chronic infusion of Ang II increases arterial MCP-1 transcription and translation, both of which are upregulated within the aged aortic wall. 25 Moreover, in older nonhuman primates and rodents, arterial wall, angiotensin-converting enzyme, and Ang II are increased. 8,16 Furthermore, in rodents, chronic angiotensin-converting enzyme inhibition dramatically retards multiple features of age-associated aortic remodeling.…”

Anti—Monocyte Chemoattractant Protein-1 Gene Therapy Protects against Focal Brain Ischemia in Hypertensive Rats

“…IL-1␤ was induced by MCP-1 in human monocytes (Jiang et al, 1992), and the induction after focal brain ischemia was significantly reduced in MCP-1-knockout mice (Hughes et al, 2001). 7ND gene transfer significantly reduced several cytokines, including IL-1␤, TNF-␣, interleukin 6, transforming growth factor ␤, and MCP-1 in aorta (Inoue et al, 2002, Ni et al, 2004 and TNF-␣, transforming growth factor ␤, and MCP-1 in ischemic heart from 1 to 7 days after myocardial infarction (Hayashidani et al, 2003). Therefore, the anti-MCP-1 approach appears to suppress the induction of proinflammatory cytokines and thereby inhibit the upregulation of adhesion molecules and inflammatory cell infiltrations, which would result in attenuation of tissue injury by brain ischemia.…”