High-density lipoprotein from subjects with coronary artery disease promotes macrophage foam cell formation: role of scavenger receptor CD36 and ERK/MAPK signaling

Abstract

Although high-density lipoprotein is atheroprotective, it can become dysfunctional in chronic inflammatory conditions and increase cardiovascular risk. We previously demonstrated that HDL from subjects with documented coronary artery disease is dysfunctional and is pro-oxidant/proinflammatory in macrophages. Here we examined the influence of dysfunctional/proinflammatory HDL (piHDL) on lipid accumulation in human macrophages, in comparison to functional HDL (nHDL). Exposure of macrophages to piHDL, in contrast to nHDL, resulted in oxidative stress and marked uptake of lipids from piHDL, leading to the formation of foam cell phenotype as noted by oil red O staining with concomitant increase in total cellular cholesterol content. Using western blotting, we identified that piHDL profoundly upregulated the expression of scavenger receptor CD36 and suppressed the expression of ABCG1 and SRB1 in macrophages, thereby facilitating cholesterol influx capacity of macrophages. We then identified that CD36 did not act alone, indeed it was activated in macrophages along with ERK/MAPK, in response to piHDL, which in turn led to lipid accumulation as well as proinflammatory response via activation of NFkB and subsequent release of proinflammatory markers-TNF-ά and MMP-9. These effects were confirmed using pharmacological inhibitors for either CD36 or ERK/MAPK. Furthermore, piHDL treatment moderately activated PPAR-γ and Nrf2, the known regulators of CD36 in macrophages, suggesting that the two forms of HDL differentially regulate CD36 expression. Taken together, the results demonstrate that a novel CD36-ERK/MAPK-dependent mechanism is involved in macrophage lipid accumulation by piHDL, there by revealing the importance of functional deficiency in HDL and its potential link to atherogenesis.

Adverse effects on macrophage lipid transport and survival by high density lipoprotein from patients with coronary heart disease

“…HDL isolated from each healthy subject and CAD patient was first evaluated for its antioxidant property by assessing its ability to inhibit LDL oxidation in vitro, using fluorescence assay. The air-saline oxidation of LDL (control LDL, pooled from five healthy subjects) gave rise to a corresponding fluorescence intensity ( However, in consistent with our previous reports, [7,8] we observed dysfunctionality and proinflammatory property in HDL derived from all CAD patients (piHDL), as it failed to protect LDL from oxidation. In fact, co-incubation of LDL with piHDL enhanced LDL oxidation (∼twofold increase in fluorescence intensity).…”

“…[4,7,8,34,37] More studies are needed to determine the exact pathways and apoptotic regulatory molecules participating in this process. [4,7,8,34,37] More studies are needed to determine the exact pathways and apoptotic regulatory molecules participating in this process.…”

“…It can undergo pronounced compositional and functional modification in subjects under certain conditions associated with acute-phase response and inflammation. [7,8] HDL may be viewed as a shuttle that can be either antiinflammatory or proinflammatory, depending on its cargo of proteins, enzymes, and lipids. [5] We have recently reported that HDL from patients with established CAD, exhibits dysfunctionality with total reduction in its antioxidant property to inhibit LDL oxidation in vitro and it also stimulates pro-oxidant effects in human monocytes.…”

“…Further characterization demonstrated an exclusive association of a protease, matrix metalloproteinase-9 with dysfunctional HDL. [7,8] HDL may be viewed as a shuttle that can be either antiinflammatory or proinflammatory, depending on its cargo of proteins, enzymes, and lipids. [9] HDL normally plays a cardioprotective role by promoting RCT which is a multi-step process resulting in the net movement of cholesterol from peripheral tissues back to the liver via the plasma compartment.…”

“…Recently, we have demonstrated that unlike HDL from healthy subjects, dysfunctional-HDL derived from subjects with CAD promotes macrophage foam cell formation. [7] This proathergenic property of lipid accumulation exhibited by the dysfunctional HDL may also adversely affect macrophage survival and even promote macrophage death.…”