Adenosine and the Cardiovascular System

Allison B. Reiss; David Grossfeld; Lora J. Kasselman; Heather A. Renna; Nicholas A. Vernice; Wendy Drewes; Justin Konig; Steven E. Carsons; Joshua DeLeon

Disclosures

Am J Cardiovasc Drugs. 2019;19(5):449-464. 

In This Article

Adenosine in Inflammation and Cholesterol Homeostasis

Methotrexate, a drug that raises adenosine levels, is used as first-line therapy to treat rheumatoid arthritis due to its anti-rheumatic and anti-inflammatory properties.[153,154] In addition, it can improve survival in rheumatoid arthritis patients because of its beneficial anti-atherogenic effects, reducing atherosclerosis-mediated cardiovascular complications, which are common in the rheumatoid arthritis population. Micha et al.[155] compiled data from ten observational studies totaling 66,334 subjects, and showed that methotrexate at a median dosage of 13–15 mg/week can reduce cardiovascular disease risk by 21% and lower myocardial infarction risk by 18%, in patients with systemic inflammation. A meta-analysis by Roubille et al.[156] examined cardiovascular outcomes in persons with rheumatoid arthritis, psoriasis or psoriatic arthritis on anti-rheumatic drugs. The primary outcome assessed was the link between treatment and all cardiovascular events. In the rheumatoid arthritis patients, those treated with methotrexate saw a 28% reduction in the risk of cardiovascular events, while tumor necrosis factor (TNF) inhibitors led to a 30% reduction. Studies have shown that methotrexate can confer up to a 70% reduction in mortality in patients with rheumatoid arthritis, with a substantial decrease in cardiovascular death.[157]

There is much evidence to support the importance of adenosine release as a mechanism through which methotrexate confers cardiovascular benefits. The inflammatory state in rheumatoid arthritis and other autoimmune disorders may promote the onset of vascular injury and atherosclerosis and some of the consequences may be mitigated by methotrexate via adenosine.[158] Methotrexate can increase extracellular adenosine at sites of inflammation, decrease attachment of leukocytes and neutrophils to endothelium and fibroblasts, as well as decrease the expression of inflammatory cytokines and complement pathways that exacerbate lesions and fatty plaque build-up.[159–161] It has been shown that inflammatory processes involving leukocytes and neutrophils play a key role in formation of atheroma and, in the case of neutrophils, in clot formation.[162–164] Anti-inflammatory effects of methotrexate are seen in a rabbit model of atherosclerosis with carotid artery stenting where methotrexate-treated rabbits displayed reduced neointimal thickness and decreased serum cytokines and adhesion molecules.[165,166]

Although adenosine has many anti-inflammatory effects, activation of adenosine receptors on cells of the immune system can induce both pro- and anti-inflammatory responses.[31,32] The concentration of adenosine, affinity of the receptor, proportion of each receptor subtype and cell type may all contribute to determining the relative pro-inflammatory/anti-inflammatory response to adenosine.[167,168] For example, the A2B receptor, a low-affinity adenosine receptor, is anti-inflammatory when inflammation is acute, but may contribute to the inflammatory state when high adenosine levels persist in chronic diseases such as pulmonary fibrosis where A2B receptors in lung fibroblasts may be pro-fibrotic.[169–171] The biological effects of adenosine occur as a result of the interaction with 4 G-protein–coupled receptors and the Gi inhibitory G protein or the Gs the stimulatory G protein, resulting in decreased or increased cAMP.[138] The A2B receptor has been proposed to interact not only with Gs, but with Gq proteins to activate phospholipase C, causing increased protein kinase C activation and elevation of intracellular calcium, leading to an inflammatory response.[172]

Since the A1 receptor, associated with pro-inflammatory activity, displays high affinity for adenosine, at low adenosine concentrations, the pro-inflammatory effect of the A1 receptor may predominate, whereas at higher plasma concentrations the anti-inflammatory effect of other receptors predominates. In this manner, increasing levels of adenosine would serve as a negative feedback on the immune system.[173,174] Underscoring this phenomenon, while adenosine has been shown to inhibit neutrophil adhesion and migration through activation of the A2A and A2B receptors, activation of the A1 and A3 receptors on neutrophils enhances chemotaxis and promotes inflammation.[175,176] In monocytes/macrophages, adenosine effects are largely anti-inflammatory. Adenosine decreases secretion of the pro-inflammatory cytokines interleukin-2, TNF-α and interferon-γ (IFN-γ), thus promoting differentiation of monocytes to the anti-inflammatory M2 phenotype.[177–179] This is consistent with findings that adenosine is atheroprotective via modulation of macrophage behavior in the arterial wall, as discussed here.

Anti-inflammatory effects of methotrexate resulting from A2A receptor activation may lead directly to its vasculoprotective properties and also to its ability to improve lipid handling.[180] A number of atheroprotective proteins involved in reverse transport of cholesterol from the periphery to the liver for excretion are upregulated by methotrexate via adenosine (Figure 3). One of these key mediators in cholesterol homeostasis is the membrane transporter ATP-binding cassette subfamily A member 1 (ABCA1), involved in active transport of cholesterol and phospholipids to extracellular apolipoprotein (apo)A-I.[181,182] In humans, homozygous or compound heterozygous mutations in the ABCA1 gene manifest as Tangier disease, described as profoundly reduced levels of high-density lipoprotein, hepatosplenomegaly, cholesterol deposition in various tissues, and a high occurrence of atherosclerotic cardiovascular disease.[183,184]

Figure 3.

MTX-induced adenosine upregulation attenuates atherosclerotic risk. Treatment with MTX increases adenosine production, which acts via the A2A receptor to upregulate various cholesterol efflux transporter proteins found on the macrophage cell membrane, namely, ABCA1 (a), which effluxes intracellular cholesterol in the form of apoA-1; ABCG1 (b), which effluxes intracellular cholesterol in the form of HDL; and 27OH (c), which effluxes intracellular cholesterol in the form of 27-hydroxycholesterol. The formation and subsequent efflux of each of these cholesterol byproducts decrease the risk of lipid overload and foam cell formation of the macrophage, thereby decreasing the risk of atherosclerosis and eventual onset of cardiovascular disease. 27OH 27-hydroxylase, ABCA1 ATP-binding cassette transporter A1, ABCG1 ATP-binding cassette transporter G1, apoA-1 apolipoprotein A-1, ATP adenosine triphosphate, HDL highdensity lipoprotein, MTX methotrexate

Another important mediator in cholesterol homeostasis, ABCG1, promotes cholesterol efflux to nascent HDL.[185,186] Adenosine agonist treatment of macrophages increases ABCG1-dependent efflux and lowers foam cell formation.[187] This transporter works together with ABCG1 in reverse cholesterol transport.[188] ABCA1 may covalently modify lipid-deficient apoA-I to create HDL, thus allowing ABCG1 to transport cholesterol to this new HDL.[189]

The cytochrome P450 cholesterol 27-hydroxylase is a third crucial reverse cholesterol transport protein involved in extrahepatic cholesterol metabolism. This enzyme modifies cholesterol into oxygenated forms such as 27-hydroxycholesterol, a more polar product that easily exits the cell.[190] ABCA1, ABCG1 and cholesterol 27-hydroxylase help move cholesterol out of cells to be degraded by the liver into bile acids for excretion, and all are upregulated by adenosine acting via the A2A receptor.[187,191] Further, oxysterols such as 27-hydroxycholesterol serve yet another role by functioning as signaling molecules that enhance expression of ABCA1 and ABCG1.[192] These oxysterols activate the ABCA1 promoter and induce ABCA1 messenger RNA (mRNA) expression via the nuclear transcription factor liver X receptor (LXR).[193,194] Costet et al.[195] showed that ABCA1 mRNA levels increase in macrophages treated with oxysterols. Fu et al.[196] found a dose-dependent rise in ABCA1 and ABCG1 via addition of exogenous LXR ligands and cholesterol loading, confirming that oxysterols upregulate reverse cholesterol transport proteins via LXR.[197] In the THP-1 human macrophage cell line, addition of the pro-inflammatory cytokine IFN-γ induces an activated, atherogenic state with suppression of 27-hydroxylase and ABCA1 and stimulation of foam cell formation.[198] Occupancy of A2A receptors by adenosine agonists counteracts the suppression of cholesterol 27-hydroxylase and ABCA1 levels, increasing both 27-hydroxylase and ABCA1 mRNA expression by about 80% in THP-1 differentiated macrophages. Foam cell formation also decreased by between 25 and 40%. This occurs via a pathway involving PKA and cAMP.[199,200]

The multiple advantageous effects of adenosine A2A receptor agonism on cholesterol transport and processing through ABC genes and 27-hydroxylase, coupled with anti-inflammatory actions of A2A receptor ligands, open the possibility of using specific A2A agonists as treatment for atherosclerotic cardiovascular disease.[201,202] The structure of the receptor is well-characterized and a number of agonists have been developed;[203] the selective A2A agonist regadenoson is the preferred vasodilator stress agent used in the United States.[204] Newer drugs that specifically target the A2A Receptor and can be administered orally may be candidates for future cardioprotection trials.[205,206]

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