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ABSTRACT
Since the first descriptions of their active functions more than ten years ago, small non-coding RNA species termed microRNA (miRNA) have emerged as essential regulators in a broad range of adaptive and maladaptive cellular processes. With an exceptionally rapid pace of discovery in this field, the dysregulation of many individual miRNAs has been implicated in the development and progression of various cardiovascular diseases. MiRNA are also expected to play crucial regulatory roles in the progression of pulmonary vascular diseases such as pulmonary hypertension (PH), yet direct insights in this field are only just emerging. This review will provide an overview of pulmonary hypertension and its molecular mechanisms, tailored for both basic scientists studying pulmonary vascular biology and physicians who manage PH in their clinical practice. We will describe the pathobiology of pulmonary hypertension and mechanisms of action of miRNA relevant to this disease. Moreover, we will summarize the potential roles of miRNA as biomarkers and therapeutic targets as well as future strategies for defining the cooperative actions of these powerful effectors in pulmonary vascular disease.
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Fig. 1.
MicroRNA (miRNA) biogenesis and mechanism of action. MiRNAs undergo several nuclear and cytosolic processing steps before maturation to a biologically active form (19-24 nt). After processing, the mature miRNA is incorporated into the RNA?induced silencing complex (RISC). Through binding to the complementary sites in the 3’ untranslated region of their target genes, miRNA promote down? regulation of the protein synthesis via translational repression or messenger RNA (mRNA) degradation.
Fig. 2.
Role of microRNAs (miRNAs) in cardiovascular disease. (A) Control of cardiomyocyte function by miRNA. The pathogenic events influencing cardiomyocytes in ischemic and hypertrophic diseases are closely controlled by multiple miRNA which regulate cell survival, apoptosis, angiogenesis, fibrosis, and remodeling.14) (B) Control of vascular function by miRNA. Pathophenotypes in diseased vasculature are closely controlled by miRNA, which regulate vascular integrity and remodeling.15,16) From White K, et al. Pulm Circ. 2012;2:278-90, with permission of Pulmonary Circulation.17)
Fig. 3.
Pathobiology of pulmonary hypertension. Multiple vascular cell types in the pulmonary arterial wall and pulmonary arterial circulation are involved in the pathobiology of pulmonary arterial hypertension (PAH). Vascular pathology in PAH is triggered by various genetic and environmental stimuli, and initial injury to the endothelium and/or adventitial fibroblasts may activate pathogenic signaling pathways. These result in an imbalance of secreted vascular effectors that cause excessive pulmonary vasoconstriction and abnormal vascular remodeling processes. Common histological features in PAH include intimal hyperplasia, medial hypertrophy, adventitial proliferation/fibrosis, occlusion of small arteries, thrombosis in situ, and infiltration of inflammatory cells (green arrow) or progenitor cells (purple arrow). Transdifferentiation of endothelial cells or fibroblasts to vascular smooth muscle cells may contribute as well (blue arrow). These vascular changes lead to the formation of a layer of“neointima”(red arrow) and, in some cases, plexiform lesions (From Chan SY, et al. J Mol Cell Cardiol. 2008;44:14-30, with permission of PubMed Central).34)
Fig. 4.
Pathogenic mechanisms of pulmonary hypertension (PH). Complex, pathogenic mechanisms that connect genetic predisposition, acquired, and exogenous factors play a role in the downstream dysfunction/dysregulation metabolism and signaling pathways resulting in PH.
Fig. 5.
Roles of vascular effectors in the pathogenesis of pulmonary arterial hypertension (PAH). Vascular effectors have been shown to have different roles in the pathogenesis of pulmonary hypertension (PH) (From Chan SY, et al. J Mol Cell Cardiol. 2008;44:14-30, with permission of PubMed Central).34)
Fig. 6.
Validated actions of microRNA (miRNA) in pulmonary hypertension (PH). MiRNA are listed that carry confirmed functions in controlling PH in rodents and humans, as categorized by protective or pathogenic roles. Down-regulation of miR-145 protects against the development of pulmonary arterial hypertension (PAH), possibly through attenuation of myocardin expression.49) MiR-328 directly represses L-type calcium channel-α1C expression, resulting in reduction of pulmonary vasoconstrictive properties. Down-regulation of insulin growth factor 1 receptor may also contribute to pulmonary artery smooth muscle cell apoptosis.50) MiR-21 down-regulates RhoB and Rho-kinase activity to protect against mechanisms driving PAH.41) An antagomir directed against miR-20a restored functional bone morphogenetic protein receptor type 2 (BMPR2) signaling preventing PAH.48) For miR-17, the BMPR2 transcript is a predicted and validated target in cultured vascular cells.47) MiR-204 directly targets Src homology 2 domain-containing tyrosine phosphatase (SHP2) expression that inhibits nuclear factor of activated T cells (NFAT) expression playing a protective role against PAH.44) Down-regulation of miR-424 and miR-503 in PAH is associated with increased fibroblast growth factor 2 (FGF2) and fibroblast growth factor receptor 1 (FGFR1) expression.51) KLF4, Kruppel-like factor-4; IGF-1, insulin-like growth factor.
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