Pharmacological profile of adenosine A2A receptors in patients with lower extremity peripheral artery disease and associated coronary artery disease: A pilot study

Abstract

BackgroundAltered blood flow occurs in patients with low extremity peripheral artery disease (LE-PAD). LE-PAD is mostly associated with coronary artery disease (CAD). Adenosine is an endogenous nucleoside that affects both coronary and limb artery blood flow, mostly via the adenosine A2A receptor (A2AR). We evaluated A2AR expression and function in peripheral blood mononuclear cells (PBMCs) and the femoral artery tissues of patients with LE-PAD. MethodsArtery tissues and PBMCs were sampled in 24 patients with intermittent claudication, and compared with PBMCs in 24 healthy subjects. Expression and function of A2AR was studied, using a A2AR antibody with agonist properties, allowing determination of A2AR affinity (KD) and cAMP production (ie.EC50). Results A2AR expression onPBMCs was lower in patients than controls (median1.3 [range 0.6-1.8]vs1.75 [1.45-2.1] arbitrary units; P<0.01), and correlated with A2AR expression in artery tissues (Pearson's r=0.71; P<0.01). Basal and maximally stimulated cAMP production of PBMCs was lower in patients vs controls: 172 [90-310]vs244 [110-380]pg/10 6 cells (P<0.05) and 375 [160-659]vs670 [410-980]pg/10 6 cells (P<0.05), respectively. A high KD/EC50 ratio, characteristic of spare receptors, was observed in CAD with inducible-myocardial-ischemia. ConclusionA2AR expression in the arteries of patients, correlated with their expression in PBMCs. A2AR expression was lower in patients than in controls. A single blood sample (for measurement of A2AR expression on PBMCs) may help to screen patients with LE-PAD, whereas the presence of spare receptors may help with risk stratification before vascular surgery in CAD patients with high risk of myocardial ischemia.

Adenosine Receptor Profiling Reveals an Association between the Presence of Spare Receptors and Cardiovascular Disorders

“…Finally, low A 2A R expression was also reported in LE-PAD patients [40]. In this population, spare A 2A R were found only when LE-PAD was associated with inducible myocardial ischemia [40]. Together, these results support a specific association between A 2A R with properties of spare receptor and myocardial ischemia.…”

“…These results also suggest that in CAD, the presence of spare A 2A R is an adaptive response to inducible ischemia. Finally, low A 2A R expression was also reported in LE-PAD patients [40]. In this population, spare A 2A R were found only when LE-PAD was associated with inducible myocardial ischemia [40].…”

“…Besides the use of a ligand with specific pharmacological properties to detect spare A 2A R, an additional point makes it feasible to indirectly evaluate an A 2A R reserve associated with cardiovascular tissues, which otherwise would require difficult, highly invasive sampling procedures, despite the strong A 2A R expression in the coronary system. Indeed, the properties of A 2A R expressed by peripheral blood mononuclear cells (PBMC) mirror the properties of its counterpart produced by cardiovascular tissues: (i) The expression of A 2A R by PBMC reflects A 2A R expression by the left ventricle in cardiac transplant recipient [38]; (ii) The expression levels of A 2A R in PBMC and in coronary and aortic tissues were found to be correlated in coronary artery disease (CAD) patients [39]; (iii) A 2A R expression evaluated on PBMCs correlates with A 2A R expression evaluated in femoral artery tissues in patients with lower extremity peripheral artery disease (LE-PAD) [40]; (iv) A 2A R expressed in PBMC and aortic tissues of CAD patients displayed a similar capacity to induce cAMP production following agonist stimulation, and hence are similarly functional [40]. These data support the conclusion that A 2A R expression and function are submitted to systemic regulation, probably because PBMC are exposed to the blood flow, communicate with coronary tissues via the lymphatic network, and consequently are submitted to adenosinergic stress as the heart and cardiovascular tissues.…”

Hyperhomocysteinemia and Cardiovascular Disease: Is the Adenosinergic System the Missing Link?

“…We showed that patients with CAD had low levels of A 2A R on the surface of peripheral blood mononuclear cells (PBMCs) [129,172,211]. PBMCs are a valuable surrogate for cardiovascular cells to study the adenosinergic profile in patients with CAD because the behavior of A 2A R in the two cell types is similar in terms of A 2A R level and cAMP production, which was reported for the left ventricle in cardiac transplant recipients, the aorta and coronary artery tissues, and femoral arteries [172,212,213]. The properties of A 2A R expressed by PBMCs mirror the properties of A 2A R in the vascular wall likely because PBMCs are exposed to blood flow and are in contact with all tissues.…”

Adenosine and Its Receptors: An Expected Tool for the Diagnosis and Treatment of Coronary Artery and Ischemic Heart Diseases

“…In CAD patients, a low A 2A R level, associated with a maximal level of cAMP production, which is consistent with the presence of spare receptors, is estimated to be associated with significant ischemia. The association between spare receptors and inducible myocardial ischemia was found in CAD patients with a positive exercise stress test in those with a positive fractional flow reserve and in patients with lower extremity peripheral artery disease, which is associated with severe CAD [ 26 , 78 , 79 ].…”