Advanced Oxidation Protein Products Accelerate Atherosclerosis Through Promoting Oxidative Stress and Inflammation

Abstract

Objective-Increased level of plasma advanced oxidation protein products (AOPPs) has been found in patients with uremia and nonuremic subjects with coronary artery disease. This study was conducted to test the hypothesis that AOPPs play a causal role in atherosclerosis. Methods and Results-Hypercholesterolemic (0.5% wt/wt diet) or normal rabbits received either repeated intravenous injections of AOPPs modified rabbit serum albumin (AOPPs-RSA) or unmodified RSA for 8 weeks. Compared with RSA-or vehicle-treated hypercholesterolemic rabbits, AOPPs-RSA-treated animals displayed increased atherosclerotic plaque area oxidized low-density lipoprotein (oxLDL) deposition, macrophage infiltration, and smooth muscle cell proliferation. Aortic sections from AOPPs-RSA-treated normal rabbits showed significant focal intima proliferation and mild Oil-Red-O staining lipid deposition in the affected areas, a phenomenon not observed in the RSA-or vehicle-treated controls. Plasma AOPPs levels in AOPPs-treated groups significantly increased in both hypercholesterolemic and normal rabbits compared with their relevant controls. Close correlations were found between plasma levels of AOPPs and the parameters of oxidative stress, eg, oxLDL and thiobarbituric acid reactive substances levels, or glutathione peroxidase activity. A highly significant correlation was also observed between plasma AOPPs and tumor necrosis factor (TNF)-␣ levels. Key Words: advanced oxidation protein products Ⅲ atherosclerosis Ⅲ hypercholesterolemia Ⅲ inflammation Ⅲ oxidative stress T he high prevalence of atherosclerotic lesions has been amply documented in patients with chronic renal failure (CRF). 1,2 However, the factors that may promote atherosclerosis in CRF patients remain to be determined. Of particular importance in this context may be the recent observation of 3 who found that advanced oxidation protein products (AOPPs) significantly increased in patients with CRF. Conclusions-ThisBiochemical characterization has revealed that AOPPs are carried by plasma proteins, especially albumin. 3 AOPPs can be formed in vitro by exposure of serum albumin to hypochlorous acid (HOCl). In vivo, plasma concentration of AOPPs closely correlated with levels of dityrosine, a hallmark of oxidized protein, and pentosidine, a marker of protein glycoxidation tightly related to oxidative stress. 4 Thus, AOPPs might be formed during oxidative stress by reaction of plasma proteins with chlorinated oxidants, and have been considered as novel markers of oxidant-mediated protein damage. 3 More interesting is the finding that AOPPs are highly correlated to carotid intima media thickness 5 and may even be related to atherosclerotic cardiovascular events. 6 More recently, increased levels of AOPPs were also found in diabetic 7,8 and nonuremic subjects with coronary artery disease, 9 suggesting that accumulation of AOPPs may be relevant in atherosclerosis and not uremia-specific. However, although the observational studies suggest a close relationship between AOPPs and atherosclerosis,...

The 18 kDa Translocator Protein as a Potential Participant in Atherosclerosis

“…As a further indication of the validity of the HFHC diet (with 3% cholesterol) applied by us, the rats in our study showed obesity as well as hyperlipidemia and steatohepatitis (DimitrovaShumkovska et al, 2010a). Parameters for enhanced oxidative stress, as we detected in plasma of our HFHC rats may correlate with inflammatory processes, including atherogenic effects observed by us and others (Witko-Sarsat et al, 1998;Liu et al, 2006;Dimitrova-Shumkovska et al, 2010a). In particular the high AOPP levels observed in the liver, plasma, and aorta, as induced by the HFHC diet, may present factors reflecting liver pathology and atherogenesis (Watanabe et al, 2004;Oettl et al, 2008;Dimitrova-Shumkovska et al, 2010a).).…”

“…However, protein oxidation products have been found in the extracellular matrix of human and animal atherosclerotic plaques (Woods et al, 2003;Li et al, 2007). The study by Liu et al (2006) was the first to our knowledge to provide in vivo evidence for a causal relationship between chronic AOPPs accumulation and atherosclerosis. This research suggests that increases in plasma AOPP, particularly in a hypercholesterolemic environment, accelerate atherosclerosis.…”

In vivo oxidized low-density lipoprotein (ox-LDL) aopp and tas after kidney transplantation: a prospective, randomized one year study comparing cyclosporine a and tacrolimus based regiments

“…The accumulation of AOPP may accelerate ox-LDL formation through enhanced OS, increased plasma TNF-α and other inflammatory mediators, enhanced macrophage invasion and smooth muscle cell proliferation in the arterial wall. Plasma AOPP elevation significantly increases atherosclerotic plaque in hypercholesterolemic rabbits and accelerates progression of atherosclerosis 30 . Of particular clinical importance is the finding that AOPPs are highly correlated with carotid intima media thickness in end-stage renal disease 31 and in peritoneal dialysis patients 32,33 .…”

Advanced oxidation protein products induce pre‐osteoblast apoptosis through a nicotinamide adenine dinucleotide phosphate oxidase‐dependent, mitogen‐activated protein kinases‐mediated intrinsic apoptosis pathway

“…It was well demonstrated that AOPPs could induce ROS generation via the activation of NADPH oxidase. (Kalousova et al., 2002; Liu et al., 2006; Weinstein & Manolagas, 2000; Witko‐Sarsat et al., 1996; Wu et al., 2016; Xie et al., 2014). We found that AOPPs could activate the NADPH oxidase and significantly increase ROS production in vitro and in vivo.…”