Adenosine Modulates HIF-1α, VEGF, IL-8, and Foam Cell Formation in a Human Model of Hypoxic Foam Cells

Abstract

Objective-Foam cell (FC) formation by oxidized low-density lipoprotein (oxLDL) accumulation in macrophages is crucial for development of atherosclerosis. Hypoxia has been demonstrated in atherosclerosis and hypoxia-inducible factor-1 (HIF-1) has been shown to promote intraplaque angiogenesis and FC development. M acrophage foam cell formation is an important process in atherosclerotic plaque development. 1 Atherosclerosis is initiated by dysfunction of endothelial cells at lesionprone sites in the walls of arteries, which results in monocyte infiltration into the arterial intima. These cells differentiated into macrophages, which then internalize large amounts of oxidized low-density lipoprotein forming cholesterol-laden macrophages called "foam cells" (FCs), which in turn give rise to fatty streaks in the arterial wall. 2 As the atherosclerotic lesion develops, the arterial wall thickness increases and oxygen diffusion into the intima is markedly reduced. These hypoxic regions contain large number of FCs revealing that these cells experience hypoxia during the development of atherosclerotic lesions. 3-4 Hypoxia-inducible factor-1 (HIF-1), the most important factor involved in the cellular response to hypoxia, is a heterodimeric transcription factor composed of an inducibly expressed HIF-1␣ subunit and a constitutively-expressed HIF-1␤ subunit. 5 It is well established that HIF plays a major role in vascular endothelial growth factor (VEGF) expression and angiogenesis, mediating important alterations associated with atherogenesis and angiogenic activity of macrophages. 6 -7 Moreover, under atherogenic conditions, the high expression of HIF-1 in macrophages promotes FC formation and atherosclerosis. 8

The A3Adenosine Receptor: History and Perspectives

“…Recently, A 3 AR stimulating degranulation has been demonstrated also in LAD2 bone marrow-derived human mast cells (Leung et al, 2014). Human eosinophils were the first cells in which native hA 3 AR was detected by using radioligand binding (Kohno et al, 1996a;Morschl et al, 2008), and this was then followed by human neutrophils (Bouma et al, 1997;Gessi et al, 2002;Chen et al, 2006;van der Hoeven et al, 2008;Corriden et al, 2013;Mulloy et al, 2013), monocytes (Broussas et al, 1999(Broussas et al, , 2002Thiele et al, 2004), macrophages (McWhinney et al, 1996;Szabo et al, 1998;Gessi et al, 2010a), foam cells (Gessi et al, 2010a), dendritic cells (Panther et al, 2001;Fossetta et al, 2003;Dickenson et al, 2003;Hofer et al, 2003), lymphocytes (Gessi et al, 2004b;Varani et al, 2009Varani et al, , 2010b, splenocytes, bone marrow cells, lymphonodes , and synoviocytes (Varani et al, 2008(Varani et al, , 2010cStamp et al, 2012). Human chondrocytes and osteoblasts, two key cell types in the skeletal system, were recently found to express A 3 AR .…”

“…However, although a genetic deficiency in the A 3 AR subtype has been demonstrated as significantly reducing the proliferative potential of aortas in organ culture, it does not attenuate the development of atherosclerotic lesions in response to a high-fat diet or vascular injury in vivo (Jones et al, 2004). On the other hand, it has been shown that, in hypoxic foam cells, adenosine stimulates HIF-1a accumulation, vascular endothelial growth factor secretion, and foam cell formation, suggesting the potential use of A 3 AR antagonists in blocking major steps in atherosclerotic plaque development (Gessi et al, 2010a).…”

“…In particular, A 3 ARs are present in different types of tumor cells, such as HL60 and K562 human leukemia , Jurkat , and U937 human lymphoma (Gessi et al, 2010a), Nb2 rat lymphoma (Fishman et al, 2000), A375 human melanoma , PGT-beta mouse tumor pineal gland (Suh et al, 2001), human glioblastoma (Merighi et al, 2006;Gessi et al, 2010b), human prostatic (Jajoo et al, 2009), and mesothelioma cells . A 3 AR subtype overexpression has also been demonstrated in colon cancer tissues, compared with normal mucosa, obtained from patients undergoing surgery (Gessi et al, 2004a;Madi et al, 2004).…”

Purinergic Signaling and Blood Vessels in Health and Disease

“…Inactivation of A 2A receptors protects apolipoprotein E-deficient mice from atherosclerosis (Wang et al, 2009a). Adenosine modulates HIF-1a, VEGF, IL-8, and foam cell formation in a human model of hypoxic foam cells (Gessi et al, 2010). The authors claim that A 2B and A 3 antagonists may be able to block steps in the atherosclerotic plaque development.…”

Role of JunB in Adenosine A2BReceptor–Mediated Vascular Endothelial Growth Factor Production

“…Although adenosine signaling through hypoxia-inducible factor-1 (HIF-1), a key transcription factor responsible for the tissue adaptation to ischemia, has been studied in detail (Merighi et al, 2005(Merighi et al, , 2006De Ponti et al, 2007;Ramanathan et al, 2007Ramanathan et al, , 2009Alchera et al, 2008;Gessi et al, 2010), the role of other transcription factors in the adenosine-dependent VEGF production is not known. In addition to HIF-1, several transcription factor-binding sites for activator protein-1 (AP-1), AP-2, early growth response-1, specificity protein 1/3, and signal transducer and activator of transcription 3 have been identified within a 1.2 kb region of both mouse and human VEGF promoters (for review, see Pages and Pouyssegur, 2005).…”