title: The microRNA-328 regulates hypoxic pulmonary hypertension by targeting at insulin growth factor 1 receptor and L-type calcium channel-α1C.
abstract: Chronic hypoxia is the most common cause of secondary pulmonary hypertension, for which the mechanisms are still unclear. Recent studies implicated an important role for microRNAs (miRNAs) in hypoxia-mediated responses in various cellular processes, including cell apoptosis and proliferation. Therefore, we hypothesized that these regulatory molecules might be implicated in the etiology of hypoxic pulmonary hypertension. Here we show that miRNA-328, a posttranscriptional regulator, was drastically downregulated in the pulmonary artery (PA) after a hypoxic assault. PA rings, Western blot, quantitative real-time PCR, in situ hybridization, and luciferase assay were used to investigate the role of miRNA-328 in hypoxic pulmonary hypertension. We found that hypoxia produced a significant inhibition of miRNA-328 expression, which was involved in PA vasoconstriction and remodeling. Overexpressing miRNA-328 in the transgenic mice remarkably decreased the right ventricular systolic pressure and PA wall thickness under both normoxia and hypoxia. MiRNA-328 inhibited L-type calcium channel-α1C expression through a miRNA-328 binding site within the 3' untranslational region of L-type calcium channel-α1C. The L-type calcium channel-α1C inhibition attenuated the PA response to KCl. Furthermore, miRNA-328 suppressed the insulin growth factor 1 receptor, ultimately leading to apoptosis of pulmonary arterial smooth muscle cells. The posttranscriptional repression of L-type calcium channel-α1C and insulin growth factor 1 receptor was further confirmed by luciferase reporter assay. These results showed that miRNA-328, an important protecting factor, plays a significant role in PA constriction and remodeling by regulating multiple gene targets in hypoxic pulmonary hypertension.
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, Second Affiliated Hospital, Harbin Medical University, Nangang District, Harbin, People's Republic of China.
authors.forename: Lei
authors.initials: L
authors.lastname: Guo
authors.forename: Zhaoping
authors.initials: Z
authors.lastname: Qiu
authors.forename: Liuping
authors.initials: L
authors.lastname: Wei
authors.forename: Xiufeng
authors.initials: X
authors.lastname: Yu
authors.forename: Xu
authors.initials: X
authors.lastname: Gao
authors.forename: Shulin
authors.initials: S
authors.lastname: Jiang
authors.forename: Hai
authors.initials: H
authors.lastname: Tian
authors.forename: Chun
authors.initials: C
authors.lastname: Jiang
authors.forename: Daling
authors.initials: D
authors.lastname: Zhu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D004195:Disease Models, Animal; D006976:Hypertension, Pulmonary / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D000860:Hypoxia / Q000150:complications / Q000503:physiopathology; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000503:physiopathology; D011651:Pulmonary Artery / Q000473:pathology / Q000503:physiopathology; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D012016:Reference Values; D012680:Sensitivity and Specificity; D014661:Vasoconstriction / Q000502:physiology
chemical_list: D020746:Calcium Channels, L-Type; D018970:Insulin-Like Growth Factor Binding Protein 1; C419385:L-type calcium channel alpha(1C); C548170:MIRN328 microRNA, human; D035683:MicroRNAs