Anti-Apolipoprotein A-1 auto-antibodies are active mediators of atherosclerotic plaque vulnerability

Abstract

These results suggest that anti-ApoA-1 IgG might be associated with increased atherosclerotic plaque vulnerability in humans and mice.

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

“…148 A few years later, Vuilleumier et al found that 11-21% of ACS patients tested positive for anti-apoA-I autoantibodies compared with 20% of patients with severe internal carotid stenosis, 38% of non-STEMI patients, 29% of patients undergoing elective carotid endarterectomy, and 1-2% of healthy controls. [149][150][151][152] In fact, there was an association between high anti-apoA-I IgG titers and increased circulating levels of oxidized LDL, TNF-α, IL-6, IL-8, and matrix metalloproteinase 9 (MMP-9). 150,153,154 Accordingly, patients positive for serum anti-apoA-I IgG had decreased plaque stability, as evidenced by increased intraplaque MMP-9 levels as well as higher densities of macrophages and neutrophils within plaques.…”

“…150,153,154 Accordingly, patients positive for serum anti-apoA-I IgG had decreased plaque stability, as evidenced by increased intraplaque MMP-9 levels as well as higher densities of macrophages and neutrophils within plaques. 151 These clinical findings are corroborated by in vivo and in vitro data showing that apoE-deficient mice immunized with anti-apoA-I IgG developed larger, more vulnerable atherosclerotic lesions with higher neutrophil and MMP-9 contents and reduced collagen content, displayed signs of myocardial injury, and had higher mortality rates than apoEdeficient mice treated with a control IgG. 151,155 Furthermore, incubation of human monocytederived macrophages with anti-apoA-I IgG under cell culture conditions resulted in increased production of cytokines (TNF-α, IL-6, IL-8), matrix metalloproteinases (MMP-9), and monocyte chemoattractants (CCL2, CXCL8).…”

“…151 These clinical findings are corroborated by in vivo and in vitro data showing that apoE-deficient mice immunized with anti-apoA-I IgG developed larger, more vulnerable atherosclerotic lesions with higher neutrophil and MMP-9 contents and reduced collagen content, displayed signs of myocardial injury, and had higher mortality rates than apoEdeficient mice treated with a control IgG. 151,155 Furthermore, incubation of human monocytederived macrophages with anti-apoA-I IgG under cell culture conditions resulted in increased production of cytokines (TNF-α, IL-6, IL-8), matrix metalloproteinases (MMP-9), and monocyte chemoattractants (CCL2, CXCL8). 151,153,154 Blocking experiments revealed that anti-apoA-I IgG-induced inflammatory responses in macrophages are mediated mainly via the CD14/TLR2 complex and to a lesser extent via TLR4.…”

“…151,155 Furthermore, incubation of human monocytederived macrophages with anti-apoA-I IgG under cell culture conditions resulted in increased production of cytokines (TNF-α, IL-6, IL-8), matrix metalloproteinases (MMP-9), and monocyte chemoattractants (CCL2, CXCL8). 151,153,154 Blocking experiments revealed that anti-apoA-I IgG-induced inflammatory responses in macrophages are mediated mainly via the CD14/TLR2 complex and to a lesser extent via TLR4. 154 Consistent with a role for TLR2 and TLR4 in the pro-atherosclerotic effects of anti-apoA-I antibodies, the augmented atherosclerotic plaque vulnerability, myocardial necrosis, and mortality in response to antiapoA-I IgG passive immunization are abrogated in TLR2-and TLR-4-deficient mice.…”

Treatment with Evasin-3 Reduces Atherosclerotic Vulnerability for Ischemic Stroke, but Not Brain Injury in Mice

“…18,22 The fold change of mRNA levels was calculated by the comparative C t method. The measured C t values were first normalized to the Hprt internal control, by calculating a delta C t (DC t ).…”