Hypoxia as a Factor Involved in the Regulation of the apoA-1, ABCA1, and Complement C3 Gene Expression in Human Macrophages

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A. M. Bogomolova^1,2, V. S. Shavva², A. A. Nikitin^1,2, E. V. Nekrasova², E. B. Dizhe², E. E. Larionova², I. V. Kudriavtsev², and S. V. Orlov^1,2,a,b*

¹St. Petersburg State University, 199034 St. Petersburg, Russia

²Institute of Experimental Medicine, 197376 St. Petersburg, Russia

^* To whom correspondence should be addressed.

Received December 10, 2018; Revised January 29, 2019; Accepted January 29, 2019

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Hypoxia plays a critical role in progression of atherosclerosis. Local oxygen deficiency in a plaque creates a specific microenvironment that alters the transcriptome of resident cells, particularly of macrophages. Reverse cholesterol transport from plaque to liver is considered a main mechanism for regression of atherosclerosis. Ubiquitously expressed ATP-binding cassette transporter A1 (ABCA1) and liver- and small intestine-derived apolipoprotein A-1 (ApoA-1) are two main actors in this process. We recently reported endogenous apoA-1 expression in human macrophages. While ABCA1 and ApoA-1 have antiatherogenic properties, the role of complement factor C3 is controversial. Plasma C3 level positively correlates with the risk of cardiovascular diseases. On the other hand, C3 gene knockout in a murine atherosclerosis model increases both plaque size and triglycerides level in blood. In the present study, we show for the first time that a hypoxia-mimicking agent, CoCl₂, induces the upregulation of the apoA-1 and C3 genes and the accumulation of intracellular and membrane protein ApoA-1 in THP-1 macrophages. The MEK1/2-Erk1/2 and MKK4/7-JNK1/2/3 cascades are involved in upregulation of ABCA1 and C3 via activation of transcription factor NF-κB, which interacts with the HIF-1α subunit of hypoxia-inducible factor 1 (HIF-1). The three major MAP-kinase cascades (Erk1/2, JNK1/2/3, and p38) and the NF-κB transcription factor are involved in the hypoxia-induced expression of the apoA-1 gene in THP-1 macrophages.

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KEY WORDS: atherosclerosis, hypoxia, macrophages, THP-1, gene expression regulation, apoA-1, ABCA1, C3

DOI: 10.1134/S0006297919050079

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