Atherosclerosis and its complications rank as the leading cause of death with the hallmarks of lipid deposition and inflammatory response. MicroRNAs (miRNAs) have recently garnered increasing interests in cardiovascular disease. In this study, we investigated the function of miR-223 and the underlying mechanism in atherosclerosis. In the atherosclerotic ApoE−/− mice models, an obvious increase of miR-223 was observed in aortic atherosclerotic lesions. In lipopolysaccharide (LPS) activated macrophages, its expression was decreased. The miR-223 overexpression significantly attenuated macrophage foam cell formation, lipid accumulation and pro-inflammatory cytokine production, which were reversed by anti-miR-223 inhibitor transfection. Mechanism assay corroborated that miR-223 negatively regulated the activation of the toll-like receptor 4 (TLR4)-nuclear factor-κB (NF-κB) pathway. Pretreatment with a specific inhibitor of NF-κB (pyrrolidinedithiocarbamate, PDTC) strikingly abrogated miR-223 silence-induced lipid deposition and inflammatory cytokine production. Furthermore, PI3K/AKT was activated by miR-223 up-regulation. Pretreatment with PI3K/AKT inhibitor LY294002 strikingly ameliorated the inhibitory effects of miR-223 on the activation of TLR4 and p65, concomitant with the increase in lipid deposition and inflammatory cytokine production. Together, these data indicate that miR-223 up-regulation might abrogate the development of atherosclerosis by blocking TLR4 signaling through activation of the PI3K/AKT pathway, and provides a promising therapeutic avenue for the treatment of atherosclerosis.
Endothelial dysfunction and inflammation are believed to be 2 primary instigators of pulmonary arterial hypertension (PH). C1q/TNF-related protein 9 (CTRP9) plays important roles in anti-inflammation and improvement of epithelial function. However, the role of CTRP9 in the progression of PH remains still unclear. In this study, the role and mechanism of CTRP9 in the PH progression were explored. First, serum CTRP9 contents and CTRP9 mRNA expression in the pulmonary artery epithelial cells from patients with PH were detected. Our data on enzyme-linked immunosorbent assay and real-time quantitative Polymerase Chain Reaction showed that CTRP9 mRNA and protein content were markedly downregulated in the patients with PH. Then the pcDNA-CTRP9 expression vector or CTRP9 siRNA was transfected into the primary pulmonary artery epithelial cells from the patients with PH in vitro. CTRP9 overexpression significantly improved endothelial NOS protein expression and reduced the secretion of endothelin-1 (ET-1) and matrix metalloproteinase-2 (MMP-2), whereas knockdown of CTRP9 sharply reduced eNOS protein expression and promoted the secretion of ET-1 and MMP-2 in the cultured human epithelial cells. Moreover, the levels of phosphatidylinositol 3-kinase (PI3K) and pAkt were reduced in the epithelial cells and CTRP9 overexpression activated the PI3K/Akt pathway. CTRP9 could inhibit cell apoptosis and eNOS expression reduction in the cells pretreated with the PI3K/Akt inhibitor LY294002 and resist LY294002-induced ET-1 and MMP-2 secretion. Finally, to verify the role of CTRP9 in the progression of PH in vivo, the pcDNA-CTRP9 expression vector or CTRP9 siRNA was intravenously injected into rats with PH. Pulmonary arterial pressures of the rats were notably reduced by the pcDNA-CTRP9 injection and elevated by the CTRP9 siRNA injection. In conclusion, CTRP9 ameliorated PH by attenuating inflammation and improving endothelial cell survival and function.
BackgroundCell-based gene therapy has become a subject of interest for the treatment of pulmonary arterial hypertension (PAH), a devastating disease characterized by pulmonary artery smooth muscle cell (PASMC) hyperplasia. Mesenchymal stem cells (MSCs) have been recently acknowledged as a potential cell vector for gene therapy. Here, we investigated the effect of MSC-based let-7a for PAH.MethodsAfter isolation and identification of MSCs from rat bone marrow, cells were infected with recombinant adenovirus vector Ad-let-7a. Lewis rats were subcutaneously injected with monocrotaline (MCT) to induce PAH, followed by the administration of MSCs, MSCs-NC (miR-control), or MSC-let-7a, respectively. Then, right ventricular systolic pressure (RVSP), right ventricular hypertrophy, and pulmonary vascular remodeling were evaluated. Rat pulmonary artery smooth muscle cells (rPASMCs) under hypoxia were co-cultured with MSCs or MSC-let-7a. Cell proliferation and apoptosis were separately determined by 3H thymidine incorporation and flow cytometry analysis. The underlying mechanism was also investigated.ResultsMSC transplantation enhanced let-7a levels in MCT-induced PAH rats. After injection with MSC-let-7a, RVSP, right ventricular hypertrophy, and pulmonary vascular remodeling were notably ameliorated, indicating a protective effect of MSC-let-7a against PAH. When co-cultured with MSC-let-7a, hypoxia-triggered PASMC proliferation was obviously attenuated, concomitant with the decrease in cell proliferation-associated proteins. Simultaneously, the resistance of PASMCs to apoptosis was remarkably abrogated by MSC-let-7a administration. A mechanism assay revealed that MSC-let-7a restrained the activation of signal transducers and activators of transcription 3 (STAT3) and increased its downstream bone morphogenetic protein receptor 2 (BMPR2) expression. Importantly, preconditioning with BMPR2 siRNA dramatically abated the suppressive effects of MSC-let-7a on PASMC proliferation and apoptosis resistance.ConclusionsCollectively, this study suggests that MSCs modified with let-7a may ameliorate the progression of PAH by inhibiting PASMC growth through the STAT3-BMPR2 signaling, supporting a promising therapeutic strategy for PAH patients.
Higher mortality in asthmatics has been shown previously. However, evidence on different asthma phenotypes on long-term mortality risk is limited. The aim was to evaluate the impact of asthma phenotypes on mortality in general population. Data from the National Health and Nutrition Examination Survey from 2001–2002 to 2013–2014 linked mortality files through December 31, 2015, were used (N = 37,015). Cox proportional hazards regression was used to estimate the risk of all-cause and cause-specific mortality adjusting for sociodemographic characteristics, smoking, body mass index, and chronic conditions. During the mean follow-up time of 7.5 years, 4326 participants died from a variety of causes. Current asthma, but not former asthma was associated with increased all-cause mortality (current asthma: HR = 1.37; 95% CI 1.20–1.58; Former asthma: HR = 0.93; 95% CI 0.73–1.18); as well as mortality from cardiovascular disease (HRCurrent = 1.41; 95% CI 1.08–1.85) and chronic lower respiratory diseases (HRCurrent = 3.17; 95% CI 1.96–5.14). In addition, we found that the HR for cardiovascular disease (CVD) mortality was slightly greater in people with childhood-onset asthma than those with adult-onset asthma. The HR for chronic lower respiratory diseases (CLRD) mortality was greater in people with adult-onset asthma than those with childhood-onset asthma. However, the differences were not statistically significant. Our study suggested that current asthma but not former asthma was associated with increased all-cause, CLRD and CVD mortality. Future well-designed studies with larger sample are required to demonstrate the association and clarify the potential mechanisms involved.
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