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-␣1C expression through a miRNA-328 binding site within the 3= untranslational region of L-type calcium channel-␣1C. The L-type calcium channel-␣1C 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-␣1C 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. Key Words: pulmonary hypertension Ⅲ miR-328 Ⅲ vasoconstriction Ⅲ apoptosis Ⅲ hypoxia P ulmonary hypertension (PH) is a challenge to modern medicine. More than 40 000 people die of primary PH each year, and more fatalities are attributed to the secondary PH. The PH is characterized by a component of abnormal pulmonary vasoconstriction and structural remodeling of the small pulmonary arteries, which undergo suppressed apoptosis and enhanced proliferation in pulmonary arterial smooth muscle cells (PASMCs).1 Both processes bring about a progressive increase in pulmonary arterial resistance, which, when fully developed, culminates in the right ventricular failure and death.2,3 Although progress has been made over the past decade, the cellular and molecular mechanisms for PH are still unclear.MicroRNAs (miRNAs), single-stranded RNAs 19 to 25 nucleotides in length, regulate several pathways, including the development, hematopoiesis, organogenesis, apoptosis, cell proliferation, and tumorigenesis. As a class of naturally occurring small and noncoding RNA molecules, miRNAs bind to the 3= untranslational region of target mRNAs and either block the translation or initiate the transcript degradation. 4 Recently, misexpression of miRNAs has been implicated in man...
Background: Tanshinone IIA inhibits the proliferation of pulmonary artery smooth muscle cells (PASMCs), but the potential mechanisms of its effects on PASMCs apoptosis remain unclear. Methods: Rat were subjected to hypoxia for 9 days with or without Tanshinone IIA treatment. PASMCs were exposed to the conditions of 2% O2 and 93% N2 for 24 h in vitro. Hematoxylin and eosin (HE) staining was used to evaluate vascular remodeling. The Cell viability was determined using cell fluorescence staining and MTT assays, and apoptosis was assessed using flow cytometry. Protein expression was quantified by Western blotting. Results: Our results showed that Tanshinone IIA treatment reduced pulmonary artery media thickening in hypoxic rats. Tanshinone IIA reduced PASMC viability in a dose-dependent manner. Additionally, Tanshinone IIA promoted PASMC apoptosis, lowered Hsp60 levels, and upregulated caspase-3 expressions under hypoxic conditions. This pro-apoptotic effect of Tanshinone IIA might be due to the reduction of the phosphorylation of JAK2/STAT3 signaling markers and the increase in the levels of the downstream target, Cx43 in PASMCs. Conclusion: These data suggest that Tanshinone IIA promotes PASMC apoptosis during hypoxia and reverses vascular remodeling. This effect is mediated by modulating the expression of Hsp60, caspase-3, and Cx43 via the JAK2/STAT3 signaling pathway. These results might provide a new therapeutic target to explore a novel strategy for hypoxia-induced vessel remodeling.
A20 is a zinc finger protein associated with hypoxia. As chronic hypoxia is responsible for intimal hyperplasia and disordered angiogenesis of pulmonary artery, which are histological hallmarks of pulmonary artery hypertension, we intended to explore the role of A20 in angiogenesis of pulmonary artery endothelial cells (ECs). Here, we found a transient elevation of A20 expression in the lung tissues from hypoxic rats compared with normoxic controls. This rapid enhancement was mainly detected in the endothelium, and similar results were reproduced in vitro. During early hypoxia, genetic inhibition of A20 increased proliferation in pulmonary artery ECs, linking to advanced cell cycle progression as well as microtubule polymerization, and aggravated angiogenic effects including tube formation, cell migration and adhesion molecules expression. In addition, a negative feedback loop between nuclear factor‐kappa B and A20 was confirmed. Our findings provide evidence for an adaptive role of A20 against pulmonary artery ECs angiogenesis via nuclear factor‐kappa B activation.
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