Regulation and Function of miR‐214 in Pulmonary Arterial Hypertension

Abstract

Dysregulation of microRNAs (miRNAs) can contribute to the etiology of diseases, including pulmonary arterial hypertension (PAH). Here we investigated a potential role for the miR-214 stem loop miRNA and the closely linked miR-199a miRNAs in PAH. All 4 miRNAs were upregulated in the lung and right ventricle (RV) in mice and rats exposed to the Sugen (SU) 5416 hypoxia model of PAH. Further, expression of the miRNAs was increased in pulmonary artery smooth muscle cells exposed to transforming growth factor β1 but not BMP4. We then examined miR-214 −/− mice exposed to the SU 5416 hypoxia model of PAH or normoxic conditions and littermate controls. There were no changes in RV systolic pressure or remodeling observed between the miR-214 −/− and wild-type hypoxic groups. However, we observed a significant increase in RV hypertrophy (RVH) in hypoxic miR-214 −/− male mice compared with controls. Further, we identified that the validated miR-214 target phosphatase and tensin homolog was upregulated in miR-214 −/− mice. Thus, miR-214 stem loop loss leads to elevated RVH and may contribute to the heart failure associated with PAH. Pulmonary arterial hypertension (PAH) is a disease characterized by narrowing of the small pulmonary arteries, leading to vascular remodeling, an elevation in pulmonary artery pressure, right ventricular hypertrophy (RVH), and heart failure. 1 Current therapies for PAH aim to reverse the endothelial dysfunction and vasoconstriction observed. 2 However, despite these therapies, PAH mortality rates remain high, and the 3-year survival of patients is only 54.9%. 3 Changes in the pulmonary vasculature are the primary cause of PAH; however, right ventricle (RV) function is a major determinant of the severity of symptoms and prognosis of pulmonary hypertension. Many therapies in development for PAH are focused on targeting the RV since heart failure is the ultimate cause of mortality in PAH. 4 PAH is predominant in females, with female ∶ male ratios of 1.4-4.1 ∶ 1. 5 Sexual dimorphism has also been observed in RV failure. Female PAH patients exhibit improved RV ejection fraction and survival compared with men. 6 This could be due at least in part to the protective effect of estrogen on RV function. 7,8 MicroRNAs (miRNAs) are involved in multiple cellular responses during normal development and disease; they act as posttranscriptional regulators to fine-tune protein synthesis. Evidence has emerged for a key role for miRNA in regulation of the cellular processes involved in PAH. We previously demonstrated that a range of miRNAs are dysregulated in rats exposed to models of PAH. 9 Later studies have shown that miR-21, the miR-143/145 cluster, miR-27a, the miR-17-92 cluster, miR-124, miR-150, miR-138, miR-190, miR-204, miR-206, miR-210, and miR-328 play a role in the development of PAH. 10 Multiple miRNAs could potentially be targeted in concert as therapeutics in PAH. 11 MicroRNA miR-214 is transcribed as a bicistronic primary transcript, which is processed to generate 4 separate mature miRNAs...

Molecular Mechanisms of Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension

“…Examination of miR expression in remodeled pulmonary arteries from patients with severe PAH identified miR-126 and miR-21 levels as being upregulated in plexiform compared to concentric lesions while expression of miR-143/145 and miR-204 were higher in concentric lesions [ 25 ]. The role of several miRs, including miR-17-92, miR-143/145, miR-204, miR-214, miR-21, and miR-130/301 in regulating PAH relevant signaling pathways and the disease phenotype has been confirmed in cellular and experimental models of the disease (reviewed in [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ]) ( Table 2 ).…”

“…miR-214 is another miR that is upregulated in the lungs and right ventricle (RV) in multiple preclinical models of PAH but, importantly, appears to have sex-related differences in how it modulates the PAH disease phenotype [ 27 , 30 ]. The miR-214 group of miRs includes four distinct mature miRNAs (miR-199-5p, miR-199-3p, miR-214-5p and miR-214-3p) that originate from a bicistronic transcript.…”

miRNA-PDGFRB/HIF1A-lncRNA CTEPHA1 Network Plays Important Roles in the Mechanism of Chronic Thromboembolic Pulmonary Hypertension

“…It has been found that miRNA-199a and miRNA-214 are highly expressed in the rat model of PH, which is associated with heart failure caused by pulmonary arterial hypertension. 36) In our final network, miRNA-199b-5p is negatively correlated with HIF1A, and it may act as a negative feedback regulator of HIF1A in CTEPH. The rest of miRNA and lncRNA related to PDGFRB and HIF1A in the final network are not yet reported to be associated with PH or CTEPH.…”

“…However, based on relevant literature, these networks may also play an important role in other types of PH. 30,31,36) In future, we will also study whether other types of PH have the same results. Secondly, we have not verified the pathways of miRNA-149-5p-PDGFRB-lncRNA CTEPHA1 and miRNA-338-5p/miRNA-199b-5p-HIF1A-lncRNA CTEPHA1 in CTEPH by PCR.…”

CrossTalk proposal: The mouse SuHx model is a good model of pulmonary arterial hypertension

“…; Stevens et al . ; Dai & Zhao, ). Thus, genetically induced alterations in metabolism and signalling in mice when coupled with the end product of PH allow testing of pathways in intact in vivo systems that can then be further evaluated in cell and tissue culture.…”