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Vascular endothelial cells contribute to the pathogenesis of cardiovascular diseases by producing and disseminating angiocrine factors. Nitric oxide (NO), catalyzed by endothelial NO synthase (eNOS), is one of the prototypical angiocrine factors. eNOS activity is modulated by site-specific phosphorylation. We have previously shown that endothelial-specific knockdown of BRG1 in Apoe –/– mice attenuates the development of atherosclerosis, in which eNOS-dependent NO catalysis plays an antagonizing role. Here we report that attenuation of atherogenesis in mice by BRG1 knockdown was accompanied by partial restoration of NO biosynthesis by 44% in the arteries and a simultaneous up-regulation of eNOS serine 1177 phosphorylation by 59%. Indeed, BRG1 depletion or inhibition ameliorated oxLDL-induced loss of NO bioavailability and eNOS phosphorylation in cultured endothelial cells. Further analysis revealed that BRG1 regulated eNOS phosphorylation and NO synthesis by activating the transcription of protein phosphatase 2A (PP2A) structural subunit a (encoded by PR65A ). BRG1 interacted with ETS1, was recruited by ETS1 to the PR65A promoter, and cooperated with ETS1 to activate PR65A transcription. Finally, depletion of ETS1, similar to BRG1, repressed PR65A induction, normalized eNOS phosphorylation, and rescued NO biosynthesis in endothelial cells treated with oxLDL. In conclusion, our data characterize a novel transcriptional cascade that regulates NO bioavailability in vascular endothelial cells.

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Objective: Nonalcoholic fatty liver disease (NAFLD) can systematically harm more aspects of human health than just the liver. In addition to the potential roles of the gut microbiota in NAFLD, commensal fungi can functionally replace intestinal bacteria in maintaining the host immune response in the gut by reversing disease susceptibility. Therefore, gut commensal fungi should be studied to help understand NAFLD. Methods: The fungal compositions of 79 patients with NAFLD and 34 matched healthy subjects were studied via internal transcribed spacer sequencing. In the NAFLD group, 32 patients underwent liver biopsies to evaluate the associations between gut fungi and NAFLD development. Results: The fungal microbiota distribution was skewed in the patients with NAFLD. The relative abundances of Talaromyces, Paraphaeosphaeria, Lycoperdon, Curvularia, Phialemoniopsis, Paraboeremia, Sarcinomyces, Cladophialophora, and Sordaria were higher in patients with NAFLD, whereas the abundances of Leptosphaeria, Pseudopithomyces, and Fusicolla were decreased. Patients with NAFLD exhibited more co-occurring fungal intrakingdom correlations. Several fungi were found to be associated with liver injury, lipid metabolism, and the development of NAFLD. Conclusions: This study found that gut fungi may play some roles in NAFLD development. Research on gut fungi may be of great value in diagnosing and monitoring NAFLD.