Molecular Imaging of Inflammation and Platelet Adhesion in Advanced Atherosclerosis Effects of Antioxidant Therapy With NADPH Oxidase Inhibition

Abstract

Background In atherosclerosis, local generation of reactive oxygen species amplifies the inflammatory response and contributes to plaque vulnerability. We used molecular imaging to test whether inhibition of NADPH oxidase with apocynin would reduce endothelial inflammatory activation and endothelial-platelet interactions, thereby interrupting progression to high-risk plaque phenotype. Methods and Results Mice deficient for both the LDL receptor and Apobec-1 were studied at 30 weeks of age and again after 10 weeks with or without apocynin treatment (10 or 50 mg/kg/day orally). In vivo molecular imaging of VCAM-1, P-selectin and platelet GPIbα in the thoracic aorta was performed with targeted contrast-enhanced ultrasound (CEU) molecular imaging. Arterial elastic modulus and pulse wave transit time were assessed using ultra-high frequency ultrasound and invasive hemodynamic measurements. Plaque size and composition were assessed by histology. Molecular imaging in non-treated mice detected a 2-fold increase in P-selectin expression, VCAM-1 expression, and platelet adhesion between 30 and 40 wks of age. Apocynin reduced all of these endothelial events in a dose-dependent fashion (25% and 50% reduction in signal at 40 weeks for low- and high-dose apocynin). Apocynin also decreased aortic elastic modulus and increased the pulse transit time. On histology, apocynin reduced total monocyte accumulation in a dose-dependent manner as well as platelet adhesion, although total plaque area was reduced in only the high-dose apocynin treatment group. Conclusions Inhibition of NADPH oxidase in advanced atherosclerosis reduces endothelial activation and platelet adhesion; which are likely responsible for the arrest of plaque growth and improvement of vascular mechanical properties.

Resveratrol attenuates vascular endothelial inflammation by inducing autophagy through the cAMP signaling pathway

“…1 Accumulating evidence indicates that AS is the result of a prolonged and excessive inflammatory process in the vascular wall, which often begins with inflammatory changes in the endothelium, characterized by the expression of adhesion molecules. [2][3][4] Pharmaceutical and dietary strategies have targeted these disorders to control AS, and many natural products with excellent pharmacological properties are good candidates for the control or prevention of AS. [5][6][7][8] Resveratrol inflammation participates centrally in all stages of atherosclerosis (as), which begins with inflammatory changes in the endothelium, characterized by expression of the adhesion molecules.…”

Increased Benefit of Interleukin-1 Inhibition on Vascular Function, Myocardial Deformation, and Twisting in Patients With Coronary Artery Disease and Coexisting Rheumatoid Arthritis

“…5,19,20 Thus, the greater improvement in coronary microcirculatory function and improvement in arterial wall properties may have also contributed to the greater improvement in LV function in our patients with CAD compared with their non-CAD counterparts.…”

“…IL-1 induces NADPH oxidase expression, 18 leading to reactive oxygen species production which in turn reduces endothelial function and favors artery vasoconstriction. 19,20 Therefore, we may speculate that a larger IL-1-driven oxidative burden may have contributed to the lower FMD and CFR observed in our patients with CAD compared with those without CAD.…”

Letter by Violi et al Regarding Article, “Molecular Imaging of Inflammation and Platelet Adhesion in Advanced Atherosclerosis Effects of Antioxidant Therapy With NADPH Oxidase Inhibition”

“…Consistent with this hypothesis are the data from another study conducted in patients with peripheral artery disease, which is a marker of systemic atherosclerosis; in that study, patients with peripheral artery disease were characterized by upregulation of NADPH oxidase activation, which was associated with lowered flow-mediated dilatation and enhanced intima-media thickness. 3 The study conducted in CGD patients is also useful in the interpretation of another interesting finding by Liu et al, 1 that is, the inhibition of platelet adhesion to the atherosclerotic plaque by apocynin treatment. Platelets from CGD had an almost complete absence of reactive oxidant species production and impaired platelet production of isoprostanes, which are proaggregating eicosanoids derived from the interaction of arachidonic acid with reactive oxidant species.…”

“…Liu et al 1 have recently demonstrated that, in an animal model of atherosclerosis, apocynin, an inhibitor of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, halted atherosclerotic progression with a mechanism involving reduced monocyte infiltration and platelet adhesion; animals prone to atherosclerosis were also characterized by impaired artery elasticity, which was reversed by apocynin treatment. These data show that atherosclerotic progression is associated with impaired artery elasticity and suggest that inhibition of NADPH oxidase may favorably affect both.…”