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Biochemistry (Moscow). Papers in Press. Published on April 1, 2019 as Manuscript BM18-346.

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

A. M. Bogomolova1,2, V. S. Shavva2, A. A. Nikitin1,2, E. V. Nekrasova2, E. B. Dizhe2, E. E. Larionova2, I. V. Kudriavtsev2, and S. V. Orlov1,2,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
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.
KEY WORDS: atherosclerosis, hypoxia, macrophages, THP-1, gene expression regulation, apoA-1, ABCA1, C3