Circulating levels of nitrated apolipoprotein A-I are increased in type 2 diabetic patients

Abstract

Recent work has shown that high-density lipoprotein (HDL) isolated from human atherosclerotic lesions and the blood of patients with established coronary artery disease contains elevated levels of 3-nitrotyrosine and 3-chlorotyrosine. A higher nitrotyrosine content in lipoprotein is significantly associated with diminished cholesterol efflux capacity of the lipoprotein. Since accelerated atherogenesis is a key complication of diabetes mellitus, and nitrosative stress has recently been implicated in diabetic pathology, we set out to demonstrate an increase in the circulating levels of nitrated apolipoprotein A (apoA)-I in type 2 diabetic patients and its putative correlation with metabolic biomarkers. In this work we addressed this hypothesis in a case-control study with 30 type 2 diabetic patients and 30 age-matched control subjects. Nitrated apoA-I was 3280+/-1910 absorbance peak area/apoA-I (g/L) for diabetic patients and 2320+/-890 for control subjects (p<0.037). This represents a 50% increase in circulating nitrated apoA-I in diabetic patients to age-matched controls. Diabetic patients also showed increases of a similar magnitude in circulating advanced glycation endproducts measured as pentosidine fluorescence (44.16+/-16.26 vs. 30.84+/-12.86 AU; p<0.01) and in circulating lipoperoxides (46.0+/-18.0 vs. 37.2+/-18.0 nmol/L; p<0.03). No significant correlation was found between nitration of apoA-I and glycosylated hemoglobin or any of the other parameters measured. If proven in subsequent functional and in vivo studies, increased nitrated apoA-I would represent another mechanism by which nitrosative stress participates in diabetic macro-angiopathy.

Advanced glycation of apolipoprotein A-I impairs its anti-atherogenic properties

“…Moreover, AGE modification is not the only apoA-I modification observed in diabetes that potentially contributes to impaired apoA-I functions. In particular, nitration and chlorination of apoA-I also occur in diabetes, damaging apoA-I functionality [13,45,46]. While the relative contribution of AGE modification to the overall effect of diabetes on apoA-I dysfunction is yet to be established, it is clear that interventions to reduce AGE levels in diabetes are anti-atherosclerotic [47].…”

“…Further, AGE modification of ABCA1 inhibits its function as well as its abundance in the macrophages of diabetic patients [12]. Another factor likely to contribute to the impairment of cholesterol efflux is the modification of HDL and apolipoprotein A-I (apoA-I) induced by factors associated with diabetes, such as nitration [13]. Simple glycation of HDL apparently does not affect its ability to promote cholesterol efflux [14]; however, non-enzymatic glycosylation of HDL has been reported to impair its ability to bind to the cell surface receptors on human fibroblasts [15] and to support the efflux of intracellular cholesterol [16].…”

In Vitro and in Vivo Protein-bound Tyrosine Nitration Characterized by Diagonal Chromatography

“…Earlier reports indeed indicated that ␣ 2 -macroglobulin was susceptible for nitration (44) and thus probably serves as a scavenger for excess radical formation. Apolipoprotein A-I is also known to be nitrated during conditions of oxidative stress because of its close association with myeloperoxidase (45)(46)(47)(48), and Tyr 43 of this protein was found nitrated. The study of Parastatidis et al (47) clearly showed that apolipoprotein A-I serves as a protector protein that scavenges radicals and controls the oxidative burden.…”

Why is HDL functionally deficient in type 2 diabetes?

“…Oxidative stress represents an integral feature of type 2 diabetes, resulting in part from the elevated production of reactive oxygen, nitrogen, and chlorine species in the arterial wall [12]. Oxidized amino acid residues, including nitrotyrosines, chlorotyrosines, oxidized lysine, and methionine residues, are present in apoA-I isolated from plasma and human atherosclerotic lesions [13••]; also, circulating levels of nitrated apoA-I are elevated in type 2 diabetic patients [14].…”

“…Also, glycated subfractions of lipoprotein containing only apoA-I (LpA-I) can be isolated from the plasma of patients with poorly controlled type 1 diabetes; apoA-I conformation is altered in such glycated HDL, resulting in decreased accessibility to anti-apoA-I monoclonal antibodies [17]. Interestingly, plasma levels of nitrated apoA-I do not correlate with those of glycated hemoglobin or any other parameter of hyperglycemia [14], suggesting that oxidative stress and hyperglycemia modify HDL through unrelated mechanisms.…”