HDL and ApoA Prevent Cell Death of Endothelial Cells Induced by Oxidized LDL

Abstract

We have previously demonstrated that toxic doses of mildly oxidized LDL evokes in cultured cells a delayed and sustained rise of cytosolic [Ca2+], eliciting in turn irreversible cell damage and leading finally to cell death. HDL and delipidated apolipoprotein (apo). A prevented effectively the toxic effect of oxidized LDL to bovine aortic endothelial cells, in a time- and dose-dependent manner. The major part of the protective effect was mimicked by purified apoA-I, whereas purified apoA-II exhibited only very low protective activity. The protective effect was independent of the paraoxonase-linked HDL activity. The protective effect of HDL is independent of the contact of HDL with oxidized LDL, as shown by preincubation of oxidized LDL with HDL or apoA. In contrast, the protective effect was dependent on the integrity of apoA and on the contact of HDL with cells, thus suggesting that HDL acts directly on cells by enhancing their resistance against oxidized LDL. Preincubation experiments show that the protective effect is dependent on the duration of the contact of cells with HDL (maximal effect observed after 12 to 16 hours' preincubation), is also dependent on protein synthesis, and is persistent for at least 48 hours after the end of the contact of HDL with cells. Finally, effective concentrations of HDL inhibit the Ca2+ peak, which is directly involved in the cytotoxic effect of oxidized LDL, as shown by the inhibitory effect of Ca2+ chelators. All together, these results suggest that HDL, mainly apoA-I, increases the resistance of endothelial cells against oxidized LDL and prevents its toxic (apoptotic) effect by blocking the pathogenic intracellular signaling (culminating in sustained Ca2+ rise) involved in cell death.

Regression of Atherosclerosis Induced by Liver-Directed Gene Transfer of Apolipoprotein A-I in Mice

“…HDL has been demonstrated in vitro to decrease neutrophil degranulation and superoxide production, 32 inhibit LDL oxidation, 33 protect endothelial cells against the effects of oxidized LDL, 34 and prevent the cytokine-induced upregulation of adhesion molecules on endothelial cells, 35 effects that have not been demonstrated to be specifically due to the apoA-I component of the HDL particle. HDL contains a variety of proteins in addition to apoA-I that have been shown to be antiatherogenic in vivo, including apoE, 19,20 apoA-IV, 21,22 LCAT, 23 CETP, 24 and paraoxonase.…”

HDL abnormalities in nephrotic syndrome and chronic kidney disease

“…Oxidative stress and inflammation are common features of CKD and promote endothelial cell injury and apoptosis. Acting via its constituent ApoA-1 and sphingosine-1 phosphate (S1P) proteins, HDL lowers caspase-3 activity, inhibits the formation of ROS, and prevents apoptosis of endothelial cells [22][23][24] . In addition, normal HDL facilitates the repair, migration, and proliferation of endothelial cells and increases the number of circulating endothelial progenitor cells -events that are essential for vascular repair and prevention of plaque formation [25][26][27] ( FIG.…”

Dysfunctional HDL: From Structure-Function-Relationships to Biomarkers

“…The situation is completely different in atherosclerotic plaques, in a high oxidative stress environment where macrophages produce high amounts of nitric oxide or peroxynitrite that could induce apoptotic cell death (Kockx and Herman 2000). In the aorta the capacity of HDL to quench endothelial cell apoptosis may therefore represent an antiatherogenic property of HDL (de Souza et al 2010;Nofer et al 2001;Suc et al 1997;Sugano et al 2000). HDL has been shown to attenuate endothelial cell apoptosis induced by different stimuli such as TNF-α, oxLDL, and growth factor deprivation (de Souza et al 2010;Nofer et al 2001;Suc et al 1997;Sugano et al 2000).…”

“…In the aorta the capacity of HDL to quench endothelial cell apoptosis may therefore represent an antiatherogenic property of HDL (de Souza et al 2010;Nofer et al 2001;Suc et al 1997;Sugano et al 2000). HDL has been shown to attenuate endothelial cell apoptosis induced by different stimuli such as TNF-α, oxLDL, and growth factor deprivation (de Souza et al 2010;Nofer et al 2001;Suc et al 1997;Sugano et al 2000). It has been suggested that HDL may inhibit both death-receptor and mitochondrial-mediated apoptotic pathways.…”