TRIM28 regulates SARS-CoV-2 cell entry by targeting ACE2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of coronavirus disease 2019, it binds to angiotensin-converting enzyme 2 (ACE2) to enter into human cells. The expression level of ACE2 potentially determine the susceptibility and severity of COVID-19, it is thus of importance to understand the regulatory mechanism of ACE2 expression. Tripartite motif containing 28 (TRIM28) is known to be involved in multiple processes including antiviral restriction, endogenous retrovirus latency and immune response, it is recently reported to be co-expressed with SARS-CoV-2 receptor in type II pneumocytes; however, the roles of TRIM28 in ACE2 expression and SARS-CoV-2 cell entry remain unclear. This study showed that knockdown of TRIM28 induces ACE2 expression and increases pseudotyped SARS-CoV-2 cell entry of A549 cells and primary pulmonary alveolar epithelial cells (PAEpiCs). In a co-culture model of NK cells and lung epithelial cells, our results demonstrated that NK cells inhibit TRIM28 and promote ACE2 expression in lung epithelial cells, which was partially reversed by depletion of interleukin-2 and blocking of granzyme B in the co-culture medium. Furthermore, TRIM28 knockdown enhanced interferon-γ (IFN-γ)- induced ACE2 expression through a mechanism involving upregulating IFN-γ receptor 2 (IFNGR2) in both A549 and PAEpiCs. The upregulated ACE2 induced by TRIM28 knockdown and co-culture of NK cells was partially reversed by dexamethasone in A549 cells. Our study identified TRIM28 as a novel regulator of ACE2 expression and SARS-CoV-2 cell entry.

Inhibition of neointimal hyperplasia in rats treated with atorvastatin after carotid artery injury may be mainly associated with down-regulation of survivin and Fas expression.

CONTEXT: Atorvastatin is a member of the drug class known as statins, which is used for lowering blood cholesterol. OBJECTIVE: The present study investigates the effect and mechanism of atorvastatin on neointimal hyperplasia after carotid artery injury (CAI) of rat. MATERIALS AND METHODS: Fifty male rats were randomly divided into four groups: control group, sham-operated group, model group, and atorvastatin treatment group. The treatment group was fed with atorvastatin (10 mg/kg) with gastro-gavage at 5 p.m. every day for 28 d after surgery. The control group, model group, and sham-operated group were fed with the same volume of distilled water instead. The proliferations of intimal and medial layers were evaluated by hematoxylin & eosin (H&E) staining. The apoptosis of vascular smooth muscle cells (VSMCs) was determined by terminal deoxynucleotidyl transferased UTP nick end labeling (TUNEL) staining. Plasma concentrations of survivin and sFas were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: Atorvastatin reduced neointimal formation and increased apoptosis of VSMCs in neointima. VSMCs apoptosis emerged at 3 d (8.42 ± 0.449 µm) and the intimal proliferation peaked by the end of 14 d (41.58 ± 1.64 µm). The plasma levels of survivin and sFas were gradually increased with the neointimal hyperplasia and increasingly decreased after atorvastatin treatment. The plasma levels of survivin and sFas in rats were elevated at 3 d (464.80 ± 105.27 pg/ml and 3256.00 ± 478.20 pg/ml, respectively), reached the peak of survivin at 14 d (1089.20 ± 232.32 pg/ml) and sFas at 7 d (4362.00 ± 639.92 pg/ml) and decreased at 28 d (562.00 ± 90.11 pg/ml and 2148.00 ± 257.14 pg/ml, respectively) in the model group. Compared with the model group, the atorvastatin treatment group has significantly less neointimal hyperplasia and more apoptosis of VSMCs. CONCLUSIONS: Atorvastatin can inhibit neointimal hyperplasia and promote SMCs apoptosis in neointimal layers, which may be mainly associated with down-regulation of survivin and Fas expression after CAI of rat.