Regulation of CD73 in the development of lower limb atherosclerosis

Abstract

Atherosclerosis is an inflammatory process of the arterial wall. CD73 (also known as ecto-5′-nucleotidase) is a key regulator of cell signaling in response to inflammation and hypoxia, and may be important in the development of atherosclerosis. Recently, we have shown that high CD73 activity can be detected in the serum of patients with peripheral arterial disease (PAD). Using this same PAD patient cohort of 226 subjects with 38 femoral artery samples obtained during surgical endarcterectomy and control artery samples taken during autopsy, we explored the association of serum CD73 activity with overall atherosclerotic burden and the expression of CD73 in mature and developing plaques. Interestingly, we found that CD73 activity had a tendency to increase along with more severe presentation of PAD (from 249 nmol/mL/h in moderate disease to 332 nmol/mL/h in severe disease; P = 0.013) and that CD73 expression is elevated in the vasa vasorum of developing plaques, but completely lost in mature occlusive plaques removed during endarcterectomy (P < 0.001). The current findings implicate that as a result of shedding and loss of CD73 from the arterial wall, CD73 activity is elevated in the serum of patients with widespread atherosclerosis. These findings highlight the importance of a better understanding of the local role of CD73 in the development and maturation of arterial atherosclerotic plaques in man.

ABCC6 deficiency promotes dyslipidemia and atherosclerosis

“…Indeed, ABCC6 activity facilitates the cellular efflux of ATP from liver and other tissues/cells 11,12 , which is sequentially converted by ENPP1 and NT5E (i.e.CD73) into pyrophosphate (PPi) and adenosine, two potent inhibitors of mineralization 5,7 . However, ATP and adenosine have numerous other biological activities, notably towards inflammation [73][74][75] and atherosclerosis [76][77][78][79][80] . Remarkably, the other enzymes downstream of ABCC6 (Fig.…”

“…Remarkably, the other enzymes downstream of ABCC6 (Fig. 8) that regulate ectopic calcification in PXE, GACI and CALJA 4,5,7,9,13,48,49,81 have also been shown to play a role in atherosclerosis development [76][77][78][79] . Of note, ENTPD1 (i.e.…”

ABCC6, Pyrophosphate and Ectopic Calcification: Therapeutic Solutions

“…Thus, understanding how ABCC6 (and NPP1) influences the homeostasis of connective tissues may one day be used to enhance tissue repair and lessen mineralization-associated morbidity and mortality in the general population. This is particularly important in light of recent reports suggesting that three of the genes in the pathway shown in Figure 1 and Figure 3 that cause ectopic calcification in PXE, GACI, and CALJA [ 6 , 8 , 9 , 10 , 11 , 17 , 18 , 20 ] have also been shown to play a role in dyslipidemia and atherosclerosis [ 93 , 94 , 222 , 223 , 224 , 225 ].…”

CD73 (Cluster of Differentiation 73) and the Differences Between Mice and Humans

“…To add complexity, serum CD73 was found to be elevated in human patients with severe peripheral artery disease, and it was also elevated in the vaso vasorum of developing plaques, however it was absent in mature occlusive PAD plaques. 90 Thus, in PAD, is the upregulation of CD73 a cause or consequence? Experimental models and tracking disease progression alongside CD73 levels in the serum are needed to determine if downregulation of CD73 contributes to PAD pathogenesis.…”