The LEPIS-HuR-TMOD4 axis regulates hepatic cholesterol homeostasis and accelerates atherosclerosis.

BACKGROUND AND AIMS: Long noncoding RNAs (lncRNAs) play important roles in the progression of atherosclerosis. In this study, we identified an uncharacterized lncRNA, Liver Expressions by PSRC1 Induced Specifically (LEPIS). This study aimed to clarify the mechanism though which LEPIS affects atherosclerosis (AS). METHODS: The expression of LEPIS and its potential target, tropomodulin 4 (TMOD4), was increased in the livers of ApoE-/- mice fed a high-fat diet (HFD). An ApoE-/- mouse model in which LEPIS or TMOD4 was overexpressed in the liver was established. The plaque load in the aorta was assessed, plasma was collected to measure blood lipid levels, and the liver was collected to study cholesterol metabolism. RESULTS: We found that both LEPIS and TMOD4 increased the AS burden and reduced hepatic cholesterol levels. A further study revealed that LEPIS and TMOD4 affected the expression of genes related to hepatic cholesterol homeostasis, including proprotein convertase subtilisin/kexin type 9 (PCSK9) and low-density lipoprotein receptor (LDLR), which are closely related to hypercholesterolemia. Mechanistically, human antigen R (HuR), an RNA-binding protein (RBP), was shown to be critical for the regulation of TMOD4 by LEPIS. Furthermore, we found that verexpression of LEPIS promoted the shuttling of HuR from the nucleus to the cytoplasm, enhanced the stability of TMOD4 mRNA, and in turn promoted the expression of TMOD4. In addition, TMOD4 was found to affect intracellular cholesterol levels through PCSK9. CONCLUSIONS: These results suggest that the LEPIS-HuR-TMOD4 axis is a potential intervention target for dysregulated hepatic cholesterol homeostasis and AS and may provide the basis for further reductions in the circulating LDL-C concentration and arterial plaque burden.

Interaction between alveolar macrophages and epithelial cells during Mycoplasma pneumoniae infection.

Mycoplasma pneumoniae, as one of the most common pathogens, usually causes upper respiratory tract infections and pneumonia in humans and animals. It accounts for 10% to 40% of community-acquired pneumonia in children. The alveolar epithelial cells (AECs) are the first barrier against pathogen infections, triggering innate immune responses by recruiting and activating immune cells when pathogens invade into the lung. Alveolar macrophages (AMs) are the most plentiful innate immune cells in the lung, and are the first to initiate immune responses with pathogens invasion. The cross-talk between the alveolar epithelium and macrophages is necessary to maintain physiological homeostasis and to eradicate invaded pathogen by regulating immune responses during Mycoplasma pneumoniae infections. This review summarizes the communications between alveolar macrophages and epithelial cells during Mycoplasma pneumoniae infections, including cytokines-medicated communications, signal transduction by extracellular vesicles, surfactant associated proteins-medicated signal transmission and establishment of intercellular gap junction channels.

Proline/serine-rich coiled-coil protein 1 inhibits macrophage inflammation and delays atherosclerotic progression by binding to Annexin A2.

BACKGROUND: Atherosclerosis (AS), the main pathological basis of life-threatening cardiovascular disease, is essentially caused by chronic macrophage inflammation. Overexpression of proline/serine-rich coiled-coil protein 1 (PSRC1) reduces macrophage inflammatory responses and delays AS development. However, the exact mechanism of PSRC1 is unclear. METHODS: Proteins interacting with PSRC1 were screened by proteomics in RAW264.7 cells, followed by RT-qPCR, immunoprecipitation and immunofluorescence to explore the specific mechanistic pathways affecting inflammation. CRISPR-Cas9 constructs for PSRC1-/- ApoE-/- (DKO) mice and high-fat diet-fed ApoE-/- and DKO mice were used for AS models for in vivo experiments. Upstream transcription factors of PSRC1 were predicted by ATAC-seq, ChIP-seq and UCSC, and the regulatory mechanism was verified by ChIP-qPCR and dual luciferase assays. Peripheral blood serum and monocytes were collected from coronary artery disease (CAD) patients and non-CAD patients. RESULTS: Increased binding of ANXA2 to PSRC1 in macrophages under oxidized low-density lipoprotein stimulation and decreased release of ANXA2 to the extracellular compartment were observed. Knockdown of ANXA2 in AS model mice delayed AS progression. Knockdown of ANXA2 in DKO mice reversed the AS-promoting effect of PSRC1 knockdown. Mechanistically, ANXA2 promotes STAT3 phosphorylation, which in turn promotes inflammatory responses. In addition, SP1 is a PSRC1 upstream repressive transcription factor, and the SP1 inhibitor mithramycin (Mith) elevated PSRC1 expression and exerted anti-AS effects in AS model mice. Patients with CAD had considerably greater serum levels of ANXA2 than those without CAD, and Mith reduced the secretion of ANXA2 in peripheral blood monocytes of CAD patients. CONCLUSION: In macrophages, PSRC1 can interact with ANXA2 to inhibit its extracellular release and delay AS development. SP1 is an upstream transcription factor of PSRC1 and inhibits the transcription of PSRC1. The SP1 inhibitor Mith can elevate PSRC1 levels and slow AS progression while reducing ANXA2 release from monocytes in CAD patients. Mith is expected to be a new agent for AS treatment.

[Serum annexin A2 level is significantly elevated in patients with coronary heart disease].

OBJECTIVE: To analyze the correlation of annexin A2 with coronary atherosclerotic heart disease (CAD) and the severity of CAD. METHODS: We collected data from a total of 200 inpatients admitted in our department between August, 2017 and August, 2019. According to the. RESULTS: of coronary angiography, the patients were divided into CAD group (n=150) and non-CAD (n=50), and the CAD patients was further divided, according to their clinical stability, into stable angina (SAP) group and acute coronary syndrome (ACS) group. Serum levels of annexin A2, MPO and PON1 were detected in all these patients, and their correlations with CAD, disease severity, and degree of coronary artery stenosis were analyzed.ResultsThe levels of annexin A2 and MPO were significantly higher in CAD patients than in non-CAD patients (P < 0.05). Among the CAD patients, those with ACS had significantly higher levels of annexin A2 (P < 0.05) and lower levels of PON-1 (P < 0.05) than those with SAP, but annexin A2 level was not significantly correlated with coronary lesion count, Gensini score, or the co-morbidity of diabetes. CONCLUSIONS: Annexin A2 is significantly elevated in patients with CAD, especially in those with ACS, and can be used as a predictor of clinical instability.