The new insight into extracellular NAD⁺ degradation‐the contribution of CD38 and CD73 in calcific aortic valve disease

Abstract

Nicotinamide adenine dinucleotide (NAD+) is crucial for cell energy metabolism and many signalling processes. Recently, we proved the role of ecto‐enzymes in controlling adenine nucleotide–dependent pathways during calcific aortic valve disease (CAVD). This study aimed to investigate extracellular hydrolysis of NAD+ and mononucleotide nicotinamide (NMN) in aortic valves and aorta fragments of CAVD patients and on the inner aortic surface of ecto‐5′‐nucleotidase knockout mice (CD73−/−). Human non‐stenotic valves (n = 10) actively converted NAD+ and NMN via both CD73 and NAD+‐glycohydrolase (CD38) according to our analysis with RP‐HPLC and immunofluorescence. In stenotic valves (n = 50), due to reduced CD73 activity, NAD+ was degraded predominantly by CD38 and additionally by ALP and eNPP1. CAVD patients had significantly higher hydrolytic rates of NAD+ (0.81 ± 0.07 vs 0.56 ± 0.10) and NMN (1.12 ± 0.10 vs 0.71 ± 0.08 nmol/min/cm2) compared with controls. CD38 was also primarily engaged in human vascular NAD+ metabolism. Studies using specific ecto‐enzyme inhibitors and CD73−/− mice confirmed that CD73 is not the only enzyme involved in NAD+ and NMN hydrolysis and that CD38 had a significant contribution to these pathways. Modifications of extracellular NAD+ and NMN metabolism in aortic valve cells may be particularly important in valve pathology and could be a potential therapeutic target.

The CD73 immune checkpoint promotes tumor cell metabolic fitness

“…Considering that CD38 can cooperate with CD73 for extracellular ADO production (35), it would be of interest to assess the impact of host CD38 on CD73-mediated tumor cell metabolic fitness. Of note, while some studies suggested that CD73 may hydrolyze extracellular NAD+ (19, 36), we and others (22) did not observe this.…”

“…Considering that CD38 can cooperate with CD73 for extracellular ADO production (35), it would be of interest to assess the impact of host CD38 on CD73-mediated tumor cell metabolic fitness. Of note, while some studies suggested that CD73 may hydrolyze extracellular NAD+ (19,36), we and others (22) did not observe this. Consistent with the observed decrease in intracellular NAD pools, and the importance of NAD for glycolysis (37)(38)(39)(40)(41), we found that CD73-deficient tumor cells also displayed impaired maximal glycolytic capacity following oligomycin treatment, which inhibits ATP synthase and forces cells to redirect pyruvate to lactate conversion via glycolysis (38).…”

The CD73 immune checkpoint promotes tumor cell metabolic fitness

“…Considering that CD38 can cooperate with CD73 for extracellular ADO production ( Morandi et al, 2018 ), it would be of interest to assess the impact of host CD38 on CD73-mediated tumor cell metabolic fitness. Of note, while some studies suggested that CD73 may hydrolyze extracellular NAD+ ( Garavaglia et al, 2012 ; Jablonska et al, 2021 ), we and others ( Wilk et al, 2020 ) did not observe this.…”