Heme and lipid peroxides in hemoglobin-modified low-density lipoprotein mediate cell survival and adaptation to oxidative stress

Abstract

Low-density lipoprotein (LDL) oxidation mediated by a variety of catalysts in atherosclerotic lesions plays a crucial role in the genesis and evolution of atherosclerotic plaques. In this study we focused on oxidative properties of hemoglobin (Hb)-modified LDL because Hb is present in atherosclerotic lesions. Under low oxygen tensions Hb was previously found to modify apolipoprotein B100 with covalent binding of Hb fragments and formation of electronegative LDL particles (LDL ؊ ). Here we show that HbLDL is highly susceptible to oxidation, but is not cytotoxic to vascular cells, as was found for LDL ؊ isolated from human plasma. HbLDL and LDL ؊ have similar levels of oxidized lipid products and low uptake rates; however, the virtual absence of HbLDL-induced toxicity depends on a marked adaptive oxidative stress response. This was evidenced by a time-and dose-dependent induction of heme oxygenase (HO-1)

The role of red blood cells in the progression and instability of atherosclerotic plaque

“…Hemoglobin also has the potential of oxidizing low density lipoproteins (LDL) [47]. Moreover, it is known that hemoglobin inactivates nitric oxide, a potent mediator of vascular homeostasis [48].…”

Proteomic Modification by Nitric Oxide

“…The biological role of heme has been reviewed extensively (47,48), and the heme molecule has been shown to promote most biological oxidation processes involved in oxygen transport, mitochondrial respiration, drug metabolism, steroid biosynthesis, cellular antioxidant defenses, and signal transduction processes (49,50). The presence of heme and peroxides may modulate vascular cell survival and oxidative stress adaptation, thus providing a possible mechanism for the evolution of atherosclerotic lesions (51). Heme is a complex of protoporphyrin IX with iron that is pentacoordinated and in the high-spin Fe (III) oxidation state.…”

One-Year Conservative Care Using Sodium Bicarbonate Supplementation Is Associated with a Decrease in Electronegative LDL in Chronic Kidney Disease Patients: A Pilot Study

“…In this context, an increased proportion of electronegative LDL [LDL(-)], a minimally oxidized lipoprotein, has been detected in CKD patients on dialysis, as compared with healthy individuals [1]. It is noteworthy that this lipoprotein has also been documented in patients at high cardiovascular risk as in familial hypercholesterolemia [2], hypertriglyceridemia [3,4], diabetes, [5,6,7,8,9,10,11], as well as in renal patients [12,13,14]. The LDL modification, which confers negative charge to the molecule, has been demonstrated to be atherogenic [15].…”