Hypoxia Is Present in Murine Atherosclerotic Plaques and Has Multiple Adverse Effects on Macrophage Lipid Metabolism

Abstract

Rationale Human atherosclerotic plaques contain large numbers of cells deprived of O2. In murine atherosclerosis, because the plaques are small, it is controversial whether hypoxia can occur. Objective To examine if murine plaques contain hypoxic cells, and whether hypoxia regulates changes in cellular lipid metabolism and gene expression in macrophages. Methods and Results Aortic plaques from apolipoprotein-E-deficient mice were immunopositive for hypoxia-inducible transcription factor (HIF-1α) and some of its downstream targets. Murine J774 macrophages rendered hypoxic demonstrated significant increases in cellular sterol and triglycerides. The increase in sterol content in hypoxic macrophages correlated with elevated 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase activity and mRNA levels. In addition, when macrophages were incubated with cholesterol complexes, hypoxic cells accumulated 120% more cholesterol, predominately in the free form. Cholesterol-efflux assays showed that hypoxia significantly decreased efflux mediated by ATP binding cassette sub-family A member 1 (ABCA1), whose sub cellular localization was altered in both J774 and primary macrophages. Furthermore, in vivo expression patterns of selected genes from cells in hypoxic regions of murine plaques were similar to those from J774 and primary macrophages incubated in hypoxia. The hypoxia-induced accumulation of sterol and decreased cholesterol efflux was substantially reversed in vitro by reducing the expression of the hypoxia-inducible transcription factor, HIF-1α. Conclusion Hypoxic regions are present in murine plaques. Hypoxic macrophages have increased sterol content due to the induction of sterol synthesis and the suppression of cholesterol efflux, effects that are in part mediated by HIF-1α.

Chronic Intermittent Hypoxia Induces Atherosclerosis via Activation of Adipose Angiopoietin-like 4

“…Macrophages take up oxidized LDL, becoming foam cells that form the atherosclerotic lesions. Macrophage foaming occurs due to HIF-1a-dependent accumulation of sterols and triglycerides and decreased cholesterol efflux (41). The main finding of our study is that Angptl4-mediated inactivation of adipose LPL and resulting hyperlipidemia is the key mechanism in the progression of atherosclerosis during CIH.…”

Hypoxia-inducible factors: key regulators of myeloid cells during inflammation

“…Hypoxia has been implicated as a pathogenic factor in atherosclerosis and contributes to the proatherosclerotic functions of macrophages ( Figure 2A) (117). Several reports showed that lipid uptake and foam cell formation are dependent on hypoxia and HIF-1α (118)(119)(120). Both murine and human macrophage cell lines increase cellular neutral lipid content when cultured under hypoxic conditions; however, this effect is reversed upon HIF-1α depletion.…”

“…PHD2 inhibition led to upregulation of LOX-1 (119). Hypoxic J774 murine macrophages exhibit elevated sterol accumulation due to (a) enhanced sterol synthesis via increased 3-hydroxy-3-methyl-glutaryl-CoA (HMGCoA) reductase activity and (b) suppressed cholesterol efflux due to altered subcellular localization of ATP-binding cassette subfamily A member 1 (ABCA1) (120). These phenotypic changes are also HIF-1α dependent.…”

Tension in the Plaque: Hypoxia Modulates Metabolism in Atheroma

“…They implicate both increased production due to augmented hydroxymethylglutaryl coenzyme A (HMG-CoA) expression and decreased efflux mediated by ATP-binding cassette A (ABCA1) function. 20 Thus, hypoxia modulates the metabolism of both triglycerides and sterolslipids that accumulate in macrophage foam cells, a hallmark of atheromata.…”