ABSTRACT
Pulmonary hypertension is a rapidly progressing disease of the lung vasculature with poor prognosis, ultimately leading to right heart failure and death. The remodeling of small pulmonary arteries represents an important pathological characteristic of pulmonary hypertension. Pulmonary arterial smooth muscle cells (PASMCs) located in the middle layer of pulmonary artery exhibit hyperproliferation and resistance to apoptosis, which is the main initiator of pulmonary vascular remodeling and similar to that seen in tumor cells. In this review we focus on the signaling pathways that play a key role in PASMCs proliferation and the latest research progress on inhibitors targeting cell proliferation pathways to provide a new perspective for the treatment of PH．
ABSTRACT
Pulmonary hypertension is characterized by the progressive increase of pulmonary arterial pressure and the gradually increasing of pulmonary vascular resistance,leading to a common disease of right heart failure and death.The pathogenesis of pulmonary hypertension has not yet been fully elucidated.The pathological feature of pulmonary arterial hypertension is the pulmonary vascular remodeling including vascular endothelial cell injury,smooth muscle cell proliferation,migration and deposition of extracellular matrix.MicroRNA is an endogenous nucleotide fragment,which can activate the expression of genes related to signal transduction through the corresponding biological behavior.Recent studies have found that microRNA plays an important role in pulmonary arterial hypertension through the injury of vascular endothelial cells,smooth muscle cell proliferation,migration and extracellular matrixdeposition.The research about microRNA that participates in the mechanism of pulmonary arterial hypertension provides a new theoretical basis for the prevention and treatment of pulmonary arterial hypertension.This review focuses on progress of microRNA and the mechanisms of pulmonary arterial hypertension.
ABSTRACT
Pulmonary arterial hypertension (PAH)is a disease of unknown etiology that leads to a progressive increase in pulmonary vascular resistance (PVR),if untreated,ultimately right heart failure and high mortality.It is concerted pulmonary vascular contraction and vascular remodeling are the 2 main courses of physiology and pathology leading to PAH,especially the significant role of proliferation of pulmonary arterial smooth muscle cells.A lot of relevant factors are revealed to take a participation into regulating the proliferation of pulmonary arterial smooth muscle cells and finally PAH.
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Aim To evaluate the effects of notoginsen-oside R1 on store-operated calcium entry ( SOCE ) in pulmonary arterial smooth muscle cells ( PASMCs ) of chronic hypoxia ( CH)-and monocrotaline ( MCT)-in-duced pulmonary hypertension ( PH) rats. Methods Mn2+ quenching of Fura-2 and measurement of intra-cellular free calcium concentration ( [ Ca2+] i ) using fluo-3 were examined in PASMCs of CH-exposed and MCT-treated rats. Results ①CH-exposed and MCT-treated rats exhibited profound PH when examined 3 weeks after hypoxia exposure or MCT injection, respec-tively. ②In the presence of 3 μmol·L-1 nifedipine, 10 μmol · L-1 notoginsenoside R1 significantly re-duced cyclopiazonic acid ( CPA )-induced the percent reduction in Fura-2 fluorescence measured 500 sec af-ter application of Mn2+, the maximal rate of Mn2+quenching, the amplitude of the Ca2+ influx transient and the resting [ Ca2+] i in PASMCs of CH-exposed and MCT-treated rats. Conclusion Notoginsenoside R1 inhibits SOCE and reduces resting [ Ca2+] i in PASMCs of CH-and MCT-induced PH rats.
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Objective To explore the mechanisms of integrin β1 on connective tissue growth factor(CTGF)-induced proliferation,migration,change of cytoskeleton of pulmonary arterial smooth muscle cell(PASMC) in vitro,and to investigate the effects of CTGF-integrin β1 signal pathway on pulmonary vascular remodeling in pulmonary arterial hypertension (PAH).Methods Pulmonary artery smooth muscle cells of SD rats were cultured in vitro.WST-1 assay was used to detect the effects of anti-integrin β1 antibody on CTGF-induced proliferation of PASMC.Transwell chambers were used to observe the effects of anti-integrin β1 antibody on CTGF-induced migration of PASMC.The cytoskeletal rearrangement was observed with coomassie brilliant blue R250 staining and Confocal Lasar Scanning Microscopy (CLSM).Results Different concentration of anti-integrin β1 antibody could inhibit the proliferation of PASMC induced by CTGF,which presents concentration dependent pattern (P ＜ 0.05).The higher the concentration of anti-integrin β1 antibody,the more severity the proliferation of PASMC induced by CTGF was inhibited.and inhibition rate of PASMC proliferation was the highest at 72 hours.Anti-integrin β1 antibody(15 mg/L) decreased significantly the number of PASMC passing through Transwell induced by CTGF,compared with CTGF group (P ＜ 0.01).Meanwhile,antiintegrin β1 antibody could change cytoskeletal rearrangement of PASMC induced by CTGF.Conclusions Integrin β1mediates the proliferation,migration,cytoskeletal rearrangement of PASMC induced by CTGF.The CTGF-integrin β1signal pathway may play a key role in proliferation,migration,cytoskeletal rearrangement PASMC.
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To understand the pathophysiological mechanisms of pulmonary arterial smooth muscle cell (PASMC) proliferation and extracellular-matrix accumulation in the development of pulmonary hypertension and remodeling, this study determined the effects of different doses of adrenomedullin (ADM) and adrenotensin (ADT) on PASMC proliferation and collagen synthesis. The objective was to investigate whether extracellular signal-regulated kinase (ERK1/2) signaling was involved in ADM- and ADT-stimulated proliferation of PASMCs in 4-week-old male Wistar rats (body weight: 100-150 g, n=10). The proliferation of PASMCs was examined by 5-bromo-2-deoxyuridine incorporation. A cell growth curve was generated by the Cell Counting Kit-8 method. Expression of collagen I, collagen III, and phosphorylated ERK1/2 (p-ERK1/2) was evaluated by immunofluorescence. The effects of different concentrations of ADM and ADT on collagen I, collagen III, and p-ERK1/2 protein expression were determined by immunoblotting. We also investigated the effect of PD98059 inhibition on the expression of p-ERK1/2 protein by immunoblotting. ADM dose-dependently decreased cell proliferation, whereas ADT dose-dependently increased it; and ADM and ADT inhibited each other with respect to their effects on the proliferation of PASMCs. Consistent with these results, the expression of collagen I, collagen III, and p-ERK1/2 in rat PASMCs decreased after exposure to ADM but was upregulated after exposure to ADT. PD98059 significantly inhibited the downregulation by ADM and the upregulation by ADT of p-ERK1/2 expression. We conclude that ADM inhibited, and ADT stimulated, ERK1/2 signaling in rat PASMCs to regulate cell proliferation and collagen expression.
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Objective To study the effect of hypoxial endothelia cell conditional medium(HECCM)on the proliferation of pulmonary arterial muscle cell(PASMC).Methods MTT assay was used to test the proliferation,immuno-cytochemistry was used to identify the expression of ?-SM-actin.Results(1)HECCM could promote the proliferation of PASMC,down-regulate their expression of ?-SM-actin.(2)DDPH could up-regulate the expression of ?-SM-actin in PASMC which was time-dependant.Conclusions DDPH could reverse the phenotype transformation of PASMC exposed to HECCM,the action was time-dependant.After some time DDPH could reversly transform PASMC to the normal contractile phenotype.
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Objective To compare the growth curve, protein content, calcium ion content of pulmonary arterial smooth muscle cells (PASMCs) cultured by enzyme digestion and tissue-sticking methods. To investigate whether PASMCs cultured by two ways could be offered to one series of signaling pathway studies. Methods The protein content was determined by upgraded-lowry, the calcium ion content by fluorescence indicator. The growth of PASMCs was observed by light microscope. Results There existed certain difference in protein content, growth curve between PASMCs cultured by the two methods, especially in calcium ion content (P
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Objective To observe the changes of Akt1,Akt2,Akt3 mRNA expression level in rat pulmonary arterial smooth muscle cells(PASMC) induced by hypoxia and to investigate the value of Akt signaling pathway in vascular reconstruction during phyoxia pulmonary hypertension(HPH).Methods The pure PASMCs were established by tissue-sticking methods.Semi-quantitative reverse transcription polymerase chain reaction(RT-PCR) were used to examine the Akt1,Akt2 and Akt3 mRNA expression after PASMCs were exposed to normoxia(21%O_2) or hypoxia(3%O_2) for 2,8,12 and 24 h respectively.Results The pure PASMCs were established.The mRNA of Akt1,Akt2,Akt3 could be detected in all groups.Exposed to hypoxia,the mRNA expression levels gradually increased,reached the peak at 8 h,then decreased,and at 24 h down to the level under normoxia.As compared with that exposed to normoxia,the mRNA expression levels of Akt1 at 2,8,12,24 h,Akt2 at 8 h,Akt3 at 8 h in PASMCs exposed to hypoxia showed significant difference(P