HYPOXIA AS A FACTOR INVOLVED IN REGULATION OF EXPRESSION <i>apoA-1</i>, <i>ABCA1 </i>AND COMPLEMENT COMPONENT C3 GENES IN HUMAN MACROPHAGES
Hypoxia plays a crucial role in atherosclerosis progression. Local decrease of oxygen availability in a plaque creates specific microenvironment that alters transcriptome in resident cells, in particular, macrophages. Reverse cholesterol transport from plaque to liver is considered to be one of the ways of atherosclerosis regression. Ubiquitously expressed ATP-binding cassette transporter A1 (ABCA1) and liver-derived apolipoprotein A-1 (ApoA-1) are two main participants of this process. Recently we have shown endogenous <i>apoA-1</i> gene expression in human macrophages. While ABCA1 and ApoA-1 possess antiatherogenic properties, the role of a complement factor C3 is controversial. Plasma C3 level positively correlates with the risk of cardiovascular diseases in humans. On the other side, <i>C3</i> gene knockout in murine atherosclerosis model results in increase both in plaque size and triglycerides content in blood. In the present work we have shown for the first time that hypoxia-mimicking agent, CoCl<sub>2</sub>, caused the upregulation of <i>apoA-1</i> and <i>C3</i> genes along with the increase in ApoA-1 intracellular and membrane content in THP-1 macrophages. MEK1/2-Erk1/2 and MKK4/7-JNK1/2/3 cascades are involved in <i>ABCA1</i> and <i>C3</i> gene upregulation via activation of NF-κB transcription factor, which synergies with HIF-1α subunit of HIF-1 (hypoxia-inducible factor 1). All three main MAP-kinase cascades (Erk1/2, JNK1/2/3, and p38) as well as NF-κB transcription factor are involved in the hypoxia-induced expression of <i>apoA-1</i> gene in THP-1 macrophages.