ABSTRACT
Pulmonary hypertension ( PH) is occult, with no distinctive clinical manifestations and poor prognosis.Pulmonary vascular remodelling is an important pathological feature in which pulmonary artery smooth muscle cell ( PASMCs) pheno- typic switching plays a crucial role.MicroRNA (miRNA) is a class of evolutionary highly conserved single-stranded small non-coding RNA.Recently, an increasing number of scholars have found that miRNA can play an important role in the occurrence and development of PH by regulating the phenotypic switching of PASMCs, which is expected to be a potential target for the prevention and treatment of PH.It has been found that miR NA such as miR-221 , miR-24, miR-15b, miR-96, miR-23a.miR-9, miR-214, miR-20a can promote the phenotypic switching of PASMCs, while miRNA such as miR-21, miR-132, miR-182, miR-449, miR-206 .miR-124, miR-30c, miR-140.miR-17-92 cluster can inhibit it.This article aims to review the research progress on miRNA that mediates PASMCs phenotypic switching in PH from both growth factor-related miRNA and hy- poxia-related miRNA.
ABSTRACT
Competition for nutrients in a polymicrobial biofilm may lead to susceptible species being subjected to nutritionalstress. The influence of bacterial growth rates and interspecies interactions on their susceptibility and response tonutritional stress is not well understood. Pseudomonas aeruginosa and Staphylococcus aureus are two prevalentcausative pathogens that coexist in biofilm-associated infections. Despite being the slower-growing species, P.aeruginosa dominates in a two-species biofilm by inducing phenotypic switching of S. aureusto a metabolicallychallenged small colony variant (SCV) via the release of 2-heptyl-4-hydroxyquinoline N-oxide (HQNO). Wehypothesize that P. aeruginosa experiences nutritional stress in competition with S. aureus, and that the release ofHQNO is an adaptive response to nutritional stress. We present an individual-based two-species biofilm model inwhich interactions between entities induce emergent properties. As the biofilm matured, the difference in growthrates of the two species caused a non-uniform distribution of nutrients leading to nutritional stress for P. aeruginosa and a concurrent increase in the proportion of S. aureus subpopulation. The latter resulted in increasedrelease of autoinducer, and subsequently the upregulation of P. aeruginosa cells via quorum sensing. UpregulatedP. aeruginosa cells released HQNO at enhanced rates, thereby inducing phenotypic switching of S. aureus toSCVs which consume nutrient at a reduced rate. This shifted the nutrient distribution back in favor of P.aeruginosa, thereby relieving nutritional stress. Increase in nutritional stress potentiated the transformation of S.aureus into SCVs. HQNO production decreased once nutritional stress was relieved, indicating that phenotypicswitching acts as a regulatory stress-adaptive response.
ABSTRACT
Objective@#To explore the influence of murine cytomegalovirus on phenotypic modulation of vascular smooth muscle cell and modulation of PI3K/Akt pathway.@*Methods@#Male apoE knockout mice were injected abdominally with 2×105 PFU MCMV, followed by 16 weeks feeding. Then aortas were sectioned for HE staining and immunohistochemical staining of smooth muscle 22 alpha (SM22α) and osteopontin (OPN). Mouse aortic smooth muscle cells(MOVAS)were incubated with MCMV, then proliferation of MOVAS and expression of SM22a and OPN were tested. Western blotting test was applied to reveal MCMV’s modulation of PI3K/Akt pathway.@*Results@#The degree of atherosclerosis of apoE-/- mice in MCMV infection group was severe than that in control group, and OPN stain positive signals predominated in the arterial wall. After 24 hours of incubation with MCMV by 3×104 PFU, the expression of SM22a decreased (P=0.023), while OPN increased (P=0.034) in MOVAS. MCMV increased expression of Akt phosphorylation compared with the control group (P=0.035). The inhibitor of PI3K pathway LY294002 not only inhibited the phenotypic modulation of smooth muscle by MCMV, but also blocked the Akt phosphorylation after MCMV infection (P=0.031), however no significant influence was observed in control group.@*Conclusions@#MCMV induces phenotypic modulation of vascular smooth muscle, PI3K/Akt signaling pathway may be involved in the process of MCMV promoting the phenotype transformation of smooth muscle cells.
ABSTRACT
Objective To explore possible role of cellular repressor of E1A-stimulated genes(CREG) in the process of phenotypic switching of adventitial fibroblasts(AFs). Methods Immunofluorescent staining was performed with tissue sections from mouse carotid arteries to evaluate the relationship between the expression of CREG and smooth muscle actin-α(α-SMA) in injured arteries, especially in the adventitia. Tissue block pasted culture method was used to isolate and culture AFs. RT-PCR and Western-blot were used to detect the change of CREG andα-SMA mRNA and protein expression in AFs in the presence of different concentrations of AngⅡfor 12 h/24 h or in the presence of 100 nmol/L Ang Ⅱ for different times. Results Normal mouse carotid arteries had little α-SMA expression throughout the tunica adventitia. Arteries at day 1 and day 3 post-injury exhibited significantly higher immunofluorescence of α-SMA compared with non-injured arteries. Alpha-SMA expression began to decrease on day 7 and progressively declined on day 14. In contrast, immunofluorescent staining revealed that CREG was expressed in the adventitia of normal arteries. Expression of CREG in the adventitia of injured arteries was decreased on the 1st day, reached its lowest value on the 3rd day, and increased gradually from the 7th day, and was higher compared with that in non-injured arteries on the 14th day after injury. Similarly, the expression of CREG in AFs was very high, and AngⅡremarkably decreased mRNA and protein expression levels of CREG in a dose-dependent and time-dependent manner. Conclusions The changes in CREG expression correlate with AF phenotypic modulation, and CREG down-regulation may facilitate AF phenotypic switching into myofibroblasts (MFs).