Chelation of copper reduces inhibition by oxidized lipoproteins of endothelium-dependent relaxation in porcine coronary arteries

Abstract

We examined the effect of dialyzing oxidized low-density lipoprotein (oLDL) against Krebs-Ringer solution, in the absence (yielding d-oLDL) or presence (yielding EDTA-oLDL) of ethylenediamine tetraacetic acid (EDTA), to investigate the mechanism that underlies the inhibition of endothelium-dependent relaxation (EDR) by o-LDL. Oxidation of LDL by exposure to Cu2+ resulted in the formation of a thiobarbituric acid-reacting substance (TBARS) and lipid hydroperoxide (LPO). At a concentration of 5 mg/dl, d-oLDL markedly attenuated EDR in the porcine coronary artery. Analysis of d-oLDL by gel filtration revealed that TBARS was ditributed in both the lipoprotein and the aqueous phases, whereas LPO was present only in the lipoprotein particles. Lysophosphatidylcholine (LPC), which has been suggested to be responsible for the impairment of EDR by oLDL, was present not only in the lipoprotein but also in the aqueous phase. However, EDR inhibitory activity was observed only in the oLDL particles, not in the aqueous phase. Almost all Cu2+ associated with the oLDL particles was removed by dialysis of oLDL against Krebs-Ringer solution containing EDTA. EDTA-oLDL or native LDL, at concentrations as high as 75 mg/dl, exerted only a moderate inhibitory action on EDR, Both TBARS and LPO in EDTA-oLDL were distributed only in the lipoprotein particles, not in the aqueous phase. These results demonstrate that the impairment of EDR by oLDL is related both to LPO and to transition metal ions such as Cu2+ associated with the lipoprotein particles, not to the amount of the TBARS or negative charge, and that factors other than LPC may affect EDR.

Vascular Effects of Ambient Pollutant Particles and Metals

“…Cuprous ion (Cu + ) destabilizes S-nitrosothiols and thus depletes cellular pool of NO [61]. Cupric ion (Cu +2 ) can oxidize low density lipoprotein to lipid hydroperoxide, which impairs endothelium-dependent relaxation of systemic vessels [62]. Other redox active metals, e.g.…”

Effects of Chelation With Edta and Vitamin B Therapy on Nitric Oxide‐related Endothelial Vasodilator Function

“…However, there is also some evidence from epidemiological studies that there may be an independent deleterious effect on vascular disease of low plasma levels of the B vitamins, specifically B6, 15,23 with 23 or without 15 a clear effect of high plasma homocysteine. 26 Because this process removes the copper by which the LDL was oxidized, the relevance of that finding in vitro is unclear, although, of course, chelation of heavy metals, particularly calcium, constituted the original basis for the use of EDTA in patients with vascular disease. 1 Percentage increase in forearm blood flow in the infused arm related to that in the non-infused arm at three dose levels of intrabrachial acetylcholine (ACh).…”

“…While there is little relevant evidence for such an effect, 6,25 it has been found that the inhibition of endothelium-dependent vascular relaxation by oxidized low-density lipoprotein (LDL) in vitro is reduced by dialysis of the oxidized LDL against EDTA. 26 Because this process removes the copper by which the LDL was oxidized, the relevance of that finding in vitro is unclear, although, of course, chelation of heavy metals, particularly calcium, constituted the original basis for the use of EDTA in patients with vascular disease. 6,25 In summary, the present study does not support a beneficial effect on NO-related endothelium-dependent vasodilator function from EDTA administration alone, at least not from 1.5 g infused twice weekly on 10 occasions, which is the lower range of that commonly used.…”