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1.
Acta Pharmacol Sin ; 40(4): 477-485, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30038339

RESUMO

Pulmonary arterial hypertension (PAH) is the most common form of pulmonary hypertension. Pulmonary arterial remodeling is closely related to the abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs), which leads to the thickening of the medial layer of muscular arteries and then results in the narrowing or occlusion of the precapillary arterioles and PAH. However, the mechanisms underlying the abnormal proliferation of PASMCs remain unclear. In this study, we established rat primary PAH models using monocrotaline (MCT) injection or hypoxic exposure, then investigated the expression patterns of seven miRNAs associated with multiple pathogenic pathways central to pulmonary hypertension, and further explored the roles and the possible mechanisms of miR-135a during the development of PAH. In the rat primary PAH models, we observed that the expression of miR-135a-5p in lungs was drastically decreased at the initial stage of PAH development after MCT administration or hypoxic exposure, but it increased by 12-fold or 10-fold at the later stage. In vitro study in PASMCs showed a similar pattern of miR-135a-5p expression, with downregulation at 6 h but upregulation at 18, 24, and 48 h after hypoxic exposure. Early, but not late, administration of a miR-135a-5p mimic inhibited hypoxia-induced proliferation of PASMCs. The protective role of early miR-135a-5p agomir in the PAH rat model further supported the hypothesis that the early decrease in the expression of miR-135a-5p contributes to the proliferation of PASMCs and development of PAH, as early administration of miR-135a-5p agomir (10 nM, i.v.) reversed the elevated mean pulmonary arterial pressure and pulmonary vascular remodeling in MCT-treated rats. We revealed that miR-135a-5p directly bound to the 3'-UTR sequence of rat transient receptor potential channel 1 (TRPC1) mRNA and decreased TRPC1 protein expression, thus inhibiting PASMC proliferation. Collectively, our data suggest that dysregulation of miR-135a-5p in PASMCs contributes to the abnormal proliferation of PASMCs and the pathogenesis of PAH. Increasing miR-135a-5p expression at the early stage of PAH is a potential new avenue to prevent PAH development.


Assuntos
Hipertensão Pulmonar/metabolismo , MicroRNAs/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Hipertensão Pulmonar/induzido quimicamente , Hipóxia , Masculino , MicroRNAs/genética , Monocrotalina , Ratos , Ratos Sprague-Dawley
2.
Zhongguo Dang Dai Er Ke Za Zhi ; 20(12): 1020-1023, 2018 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-30572991

RESUMO

OBJECTIVE: To study the protective effect of vitamin A on residual pancreatic ß cell function in children with type 1 diabetes mellitus (T1DM) and its mechanism. METHODS: A total of 46 children with T1DM (with a course of disease of 0.5-1 year) were randomly divided into an intervention group and a non-intervention group (n=23 each). The children in both groups were given insulin treatment, and those in the intervention group were also given vitamin A at a daily dose of 1 500-2 000 IU. A total of 25 healthy children were enrolled as the control group. The daily dose of insulin was calculated for the children with T1DM, and the serum levels of glycosylated hemoglobin (HbA1C), stimulated C-peptide, vitamin A, and interleukin-17 (IL-17) were measured before intervention and 3 months after intervention. RESULTS: Before vitamin A intervention, the intervention group and the non-intervention group had a significantly lower serum level of vitamin A and a significantly higher level of IL-17 than the control group (P<0.01). After 3 months of intervention, the intervention group had significantly lower serum IL-17 level and insulin dose and a significantly higher level of stimulated C-peptide than the non-intervention group (P<0.05). CONCLUSIONS: Vitamin A may protect residual pancreatic ß cell function, possibly by improving the abnormal secretion of IL-17 in children with T1DM.


Assuntos
Diabetes Mellitus Tipo 1 , Células Secretoras de Insulina , Glicemia , Peptídeo C , Hemoglobinas Glicadas , Humanos , Lactente , Insulina , Vitamina A
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