Macrophage NFATc3 prevents foam cell formation and atherosclerosis: evidence and mechanisms.

AIMS: Our previous study demonstrated that Ca2+ influx through the Orai1 store-operated Ca2+ channel in macrophages contributes to foam cell formation and atherosclerosis via the calcineurin-ASK1 pathway, not the classical calcineurin-nuclear factor of activated T-cell (NFAT) pathway. Moreover, up-regulation of NFATc3 in macrophages inhibits foam cell formation, suggesting that macrophage NFATc3 is a negative regulator of atherogenesis. Hence, this study investigated the precise role of macrophage NFATc3 in atherogenesis. METHODS AND RESULTS: Macrophage-specific NFATc3 knockout mice were generated to determine the effect of NFATc3 on atherosclerosis in a mouse model of adeno-associated virus-mutant PCSK9-induced atherosclerosis. NFATc3 expression was decreased in macrophages within human and mouse atherosclerotic lesions. Moreover, NFATc3 levels in peripheral blood mononuclear cells from atherosclerotic patients were negatively associated with plaque instability. Furthermore, macrophage-specific ablation of NFATc3 in mice led to the atherosclerotic plaque formation, whereas macrophage-specific NFATc3 transgenic mice exhibited the opposite phenotype. NFATc3 deficiency in macrophages promoted foam cell formation by potentiating SR-A- and CD36-meditated lipid uptake. NFATc3 directly targeted and transcriptionally up-regulated miR-204 levels. Mature miR-204-5p suppressed SR-A expression via canonical regulation. Unexpectedly, miR-204-3p localized in the nucleus and inhibited CD36 transcription. Restoration of miR-204 abolished the proatherogenic phenotype observed in the macrophage-specific NFATc3 knockout mice, and blockade of miR-204 function reversed the beneficial effects of NFATc3 in macrophages. CONCLUSION: Macrophage NFATc3 up-regulates miR-204 to reduce SR-A and CD36 levels, thereby preventing foam cell formation and atherosclerosis, indicating that the NFATc3/miR-204 axis may be a potential therapeutic target against atherosclerosis.

A non-immersive virtual reality-based intervention to enhance lower-extremity motor function and gait in patients with subacute cerebral infarction: A pilot randomized controlled trial with 1-year follow-up.

Introduction: This study was conducted to evaluate whether a non-immersive virtual reality (VR)-based intervention can enhance lower extremity movement in patients with cerebral infarction and whether it has greater short-term and long-term effectiveness than conventional therapies (CTs). Materials and methods: This was a single-blinded, randomized clinical controlled trial. Forty-four patients with subacute cerebral infarction were randomly allocated to the VR or CT group. All intervention sessions were delivered in the inpatient unit for 3 weeks. Outcomes were measured before (baseline) and after the interventions and at 3-month, 6-month and 1-year follow-ups. The outcomes included clinical assessments of movement and balance function using the Fugl-Meyer Assessment of Lower Extremity (FMA-LE) and Berg Balance Scale (BBS), and gait parameters in the sagittal plane. Results: In the VR group, the walking speed after intervention, at 3-month, 6-month, and 1-year follow-ups were significantly greater than baseline (p = 0.01, <0.001, 0.007, and <0.001, respectively). Compared with baseline, BBS scores after intervention, at 3-month, 6-month, and 1-year follow-ups were significantly greater in both the VR group (p = 0.006, 0.002, <0.001, and <0.001, respectively) and CT group (p = <0.001, 0.002, 0.001, and <0.001, respectively), while FMA-LE scores after intervention, at 3-month, 6-month, and 1-year follow-ups were significant increased in the VR group (p = 0.03, <0.001, 0.003, and <0.001, respectively), and at 3-month, 6-month, and 1-year follow-ups in the CT group (p = 0.02, 0.004 and <0.001, respectively). In the VR group, the maximum knee joint angle in the sagittal plane enhanced significantly at 6-month follow-up from that at baseline (p = 0.04). Conclusion: The effectiveness of the non-immersive VR-based intervention in our study was observed after the intervention and at the follow-ups, but it was not significantly different from that of CTs. In sum, our results suggest that non-immersive VR-based interventions may thus be a valuable addition to conventional physical therapies to enhance treatment efficacy. Clinical trial registration: http://www.chictr.org.cn/showproj.aspx?proj=10541, ChiCTR-IOC-15006064.