Implication of CD38/NAADP‐regulated autophagic flux in the phenotypic plasticity of mouse coronary arterial myocytes (849.3)

Abstract

We recently reported that CD38 gene deletion inhibits lysosomes trafficking and fusion with autophagosomes (APs) leading to impaired autophagic flux in mouse coronary arterial myocytes (CAMs). However, the pathogenic role of this deranged autophagic flux due to CD38 deficiency remains unknown. Here, we showed that coronary arteries from CD38‐/‐ mice even on the normal diet exhibited marked profibrotic feature with increased collagen deposition compared to CD38+/+ mice. This collagen deposition in coronary arteries was significantly enhanced when CD38‐/‐ mice were fed a Western diet. In primary cultures of CAMs from CD38‐/‐ mice, a marked increase in the level of collagen I protein, but not mRNA was found in comparison with those cells from CD38+/+ mice either under control condition or upon TGF‐β stimulation. By treatment of CAMs from CD38+/+ mice with the inhibitor of CD38 enzyme, nicotinamide or the antagonist of CD38 product‐NAADP, NED‐19, the similar phenotypic changes in CAMs were observed to those cells from CD38‐/‐ mice. This action of CD38 inhibition and gene deletion was also similar to that observed when CAMs were treated by the inhibitor of the AP formation, 3‐methyladenine or the lysosome function disruptor, bafilomycin A1. However, inhibition of proteasome function by MG132 had no effects on increased collagen I levels in CAMs. Further confocal microscopy showed that enhanced collagen I deposition was mainly within lysosomes in CD38+/+ CAMs, which was blocked by CD38 gene deletion or NAADP antagonist, NED‐19. Collectively, we can draw a conclusion from these data that collagen I metabolism is disturbed when CAMs lack CD38 gene or if CD38‐NAADP‐mediated signaling pathway is dysfunctional, which may be associated with impaired autophagic degradation of collagen I. This CD38 regulation of autophagic flux may represent a novel mechanism regulating the phenotypic plasticity of CAMs upon atherogenic stimulation.Grant Funding Source: HL057244, HL091464 and HL075316