Myeloid Krüppel-like factor 4 deficiency augments atherogenesis in ApoE-/- mice--brief report - PubMed (original) (raw)

Myeloid Krüppel-like factor 4 deficiency augments atherogenesis in ApoE-/- mice--brief report

Nikunj Sharma et al. Arterioscler Thromb Vasc Biol. 2012 Dec.

Abstract

Objective: To investigate the role of Krüppel-like factor 4 (KLF4), an essential transcriptional regulator of macrophage polarization (M1/M2), in the pathogenesis of atherosclerosis.

Methods and results: Despite the acknowledged importance of macrophages in atherosclerosis, the role of M1 (classically activated or proinflammatory) versus M2 (alternatively activated or anti-inflammatory) macrophages in this process remains incompletely understood. We recently identified KLF4 as a regulator of macrophage subset specification; that is, KLF4 promotes M2 and inhibits M1 phenotype. Here, we provide evidence that KLF4-deficient macrophages exhibit enhanced proinflammatory activation and foam cell formation in response to oxidized lipids. In vivo, myeloid KLF4-deficient mice (ApoE(-/-) background) develop significantly more vascular inflammation and atherosclerotic lesion formation.

Conclusions: Our findings identify myeloid KLF4 as an essential regulator of vascular inflammation and experimental atherogenesis.

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Figures

Figure 1

Figure 1. Myeloid KLF4 regulates the response to oxidized lipids

A) After 16hrs treatment of macrophage with IL-1β (20ng/ml), TNF-α (10ng/ml) or POV-PC (10μg/ml), KLF4 expression was analyzed by qPCR. (n=3) B) KLF4+/+ or KLF4Δ/Δ macrophages were treated with POV-PC and expression of pro-inflammatory markers iNOS, IL-6 and IL-1β was analyzed by qPCR. (n=3) C) KLF4+/+ or KLF4Δ/Δ macrophages were incubated with Dil-OxLDL (15μg/ml) for 4 hrs and uptake was analyzed by fluorescence-microscopy and flow cytometry. (n=4) D) Gene expression analysis of lipoprotein receptors in KLF4+/+ and KLF4Δ/Δ macrophages (n=4).

Figure 2

Figure 2. Myeloid KLF4 deficiency augments atherosclerosis

A&B) Representative Sudan IV staining indicating enhanced atherosclerotic lesions in KLF4Δ/ΔApoE−/− vs. KLF4Δ/ΔApoE+/+ mice on normal chow (A) and HFD (B). C&D) Quantitative analysis of lesion area on normal chow (C) and HFD (D) fed mice aortas.

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