| First Author | Zhang Y | Year | 2014 |
| Journal | Cardiovasc Res | Volume | 102 |
| Issue | 1 | Pages | 68-78 |
| PubMed ID | 24445604 | Mgi Jnum | J:229291 |
| Mgi Id | MGI:5751383 | Doi | 10.1093/cvr/cvu011 |
| Citation | Zhang Y, et al. (2014) Defective autophagosome trafficking contributes to impaired autophagic flux in coronary arterial myocytes lacking CD38 gene. Cardiovasc Res 102(1):68-78 |
| abstractText | AIM: Autophagic flux is an important process during autophagy maturation in smooth muscle cells. However, the molecular mechanisms underlying autophagic flux in these cells are largely unknown. Here, we revealed a previously undefined role of CD38, an enzyme that metabolizes NADP(+) into NAADP, in the regulation of autophagic flux in coronary arterial myocytes (CAMs). METHODS AND RESULTS: In vivo CD38 gene knockout mice (CD38(-/-)) fed the high-fat Western diet showed increased accumulation of autophagosomes in coronary arterial media compared with that in wild-type (CD38(+/+)) mice, suggesting that CD38 gene deletion results in a defective autophagic process in CAMs of coronary arteries. In primary cultured CAMs, CD38 gene deletion markedly enhanced 7-ketocholesterol (7-Ket, an atherogenic stimulus and autophagy inducer)-induced accumulation of autophagosomes and increased expression of an autophagic marker, LC3B. However, no difference in autophagosome formation was observed between CD38(+/+) and CD38(-/-) CAMs when autophagic flux was blocked, which indicates that CD38 regulates autophagic flux rather than induction of autophagosome formation. Further, 7-Ket-induced formation of autophagolysosomes was markedly attenuated in CD38(-/-) CAMs compared with CD38(+/+) CAMs. Mechanistically, CD38 gene deletion markedly inhibited 7-Ket-induced dynein activation and autophagosome trafficking, which were associated with attenuated lysosomal Ca(2+) release. Importantly, coronary arterial smooth muscle from CD38(-/-) mice fed the Western diet exhibited phenotypic changes towards a more dedifferentiated state with abnormal extracellular matrix metabolism. CONCLUSION: Taken together, these results suggest that CD38 plays a critical role in autophagosome trafficking and fusion with lysosomes, thus controlling autophagic flux in CAMs under atherogenic stimulation. |
