Abstract
Recent studies have reported that CD38 gene deficiency results in dedifferentiation or transdifferentiation of arterial smooth muscle (SMCs) upon atherogenic stimulations. However, the molecular mechanisms mediating this SMC phenotypic change remain unknown. In the present study, we first characterized the phenotypic change in the primary cultures of coronary arterial myocytes (CAMs) from CD38‐/‐ mice. It was shown that CD38 deficiency decreased the expression of contractile marker calponin and α‐SMA and increased the expression of SMC dedifferentiation marker vimentin, which was accompanied by collagen I accumulation and cell proliferation. This phenotypic change was enhanced by 7‐ketocholesterol (7‐Ket), an atherogenic stimulus in CAMs from CD38‐/‐ mice. We further found that the CD38 deficiency decreased the protein level of nuclear factor E2‐related factor 2 (Nrf2) and inhibited its activity. Given that Nrf2 is a transcription factor that responds to oxidative stress, we determined the role of redox signaling in the regulation of Nrf2 expression and activity. It was demonstrated that in CD38‐/‐ CAMs 7‐Ket failed to produce O2‐., while in CD38+/+ CAMs 7‐Ket‐induced O2‐. production was substantially attenuated by Nox4 gene silencing. In addition, 7‐Ket‐induced increase in Nrf2 activity in CD38+/+ CAMs was significantly inhibited by silencing Nox4 gene. Finally, we demonstrated that both Nrf2 gene silencing and CD38 deletion had similar effect to increase CAM dedifferentiation upon 7‐Ket stimulation. In contrast, the overexpression of Nrf2 gene markedly abolished 7‐Ket‐induced dedifferentiation in CD38‐/‐ CAMs. These results suggest that CD38 activity is required for 7‐Ket‐induced O2‐. production, which increases Nrf2 activity maintaining CAMs in a differentiated status. When CD38 gene expression and function are deficient, the Nrf2 activity is suppressed thereby leading to dedifferentiation of CAMs.Grant Funding Source: HL057244, HL091464 and HL075316
Published Version
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