<i>MicroRNAs and PARP: co-conspirators with ROS in pulmonary hypertension</i>. Focus on “miR-223 reverses experimental pulmonary arterial hypertension” (2015)

Editorial FocusMicroRNAs and PARP: co-conspirators with ROS in pulmonary hypertension. Focus on "miR-223 reverses experimental pulmonary arterial hypertension"Kimberly A. Smith, Jason X.-J. Yuan, and Paul T. SchumackerKimberly A. SmithDepartment of Pediatrics, Northwestern University, Chicago, Illinois; and , Jason X.-J. YuanDepartment of Medicine, Division of Translational and Regenerative Medicine, The University of Arizona College of Medicine, Tucson, Arizona, and Paul T. SchumackerDepartment of Pediatrics, Northwestern University, Chicago, Illinois; and Published Online:15 Sep 2015https://doi.org/10.1152/ajpcell.00209.2015This is the final version - click for previous versionMoreSectionsPDF (89 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations pulmonary arterial hypertension (PAH) is a progressive disease manifested by maladaptation of the pulmonary vasculature. The development of PAH can be influenced by genetic predisposition and/or by diverse endogenous or environmental stimuli. Regardless of the initial pathogenic factors, pulmonary vascular remodeling, sustained pulmonary vasoconstriction, in situ thrombosis, and increased pulmonary vascular wall stiffness are the major contributors to elevated pulmonary vascular resistance (PVR). The increase in PVR can lead to right ventricular failure and death in patients with PAH. While treatments for this disease are improving, it continues to be a life-threatening condition.MicroRNAs (miRNAs) have been implicated in the development and progression of PAH. MiRNAs are small, non-coding RNAs that regulate gene and protein expression by promoting degradation or suppressing translation of target mRNAs. Several studies have demonstrated aberrant expression of miRNA in patient samples and animal models of pulmonary hypertension (PH) (3, 4). A study by Caruso and colleagues (3) established that chronic hypoxia- and monocrotaline-induced PH in rats, two commonly used animal models of PH, resulted in reduced expression of miRNA-22 (miR-22), miR-30, and let-7f, while miR-322 and miR-451 were significantly increased. A study from the laboratory of Dr. Sébastien Bonnet showed that activation of STAT3 suppresses miR-204 expression, resulting in further activation of STAT3 and activation of nuclear factor of activated T cells (NFAT), together leading to excessive proliferation of pulmonary arterial smooth muscle cells (PASMC) (4). In patients with PAH or other forms of PH, deficiency in apelin, an inotropic and cardiovascular protective protein, inhibits expression of miR-424 and miR-503, resulting in increased expression of target genes, FGF2 and FGFR1, that promote proliferation of pulmonary arterial endothelial cells (PAEC) (6). A study by Bertero and colleagues (1) identified the miR-130/301 family as "master miRNAs" which regulate subordinate miRNA networks. Increased expression of miR-130/301 in PASMC modulated STAT3-miR-204 signaling, while in PAEC, miR-130/301 modulated apelin-miR-424/503-FGF2 signaling to promote PH-associated phenotypes (1). While there may be discordant patterns of miRNA regulation depending on the model of PH studied (8), these studies clearly indicate that miRNAs play a role in the development and progression of PAH. Identifying how miRNAs regulate signaling pathways important in PAH is critical to advance our understanding of this disease in order to develop new therapies for treatment.In this issue, Meloche et al. (7) report on the role of miR-223 in experimental PH. The authors first demonstrate that miR-223 expression is decreased in lung tissue, distal pulmonary arteries, and PASMC isolated from PAH patients. This nicely demonstrates that miR-223 also is relevant to the human disease even though much of the work in their study is done in experimental PH. miR-223, which is remarkably conserved across species, is a modulator of hematopoietic lineage differentiation and has been identified as a biomarker and therapeutic target in cancer and inflammation (9). In the cancer literature, PARP-1 has been shown to be a target of miR-223, and the report from the Bonnet group provides evidence that downregulation of miR-223 results in increased PARP-1 expression in PASMC from PAH patients (7). In PAH patients, hypoxia-inducible factor 1α (HIF-1α) is stabilized even under normoxic conditions, and HIF-1 is known to regulate several miRNAs (7). The Bonnet group now shows that miR-223 expression is repressed by HIF-1 and that loss of miR-223 promotes increased proliferation and decreased apoptosis in control cells. To evaluate miR-223 as a potential therapeutic target, the authors apply synthetic miR-223 molecules via intratracheal nebulization to rats with monocrotaline-induced PH. Reestablishment of miR-223 increases cardiac output, decreases vascular remodeling, and improves survival, suggesting that it may have a potential therapeutic role (7).In addition to identifying the role of miR-223, the authors' study highlights the role of DNA damage and PARP-1 activation in PH. The central dogma of poly(ADP-ribosyl)ation has been that DNA damage activates PARP-1, which facilitates DNA damage repair. However, several key discoveries have identified new biological roles for PARP-1 (2). We now know that PARP-1 can be activated by DNA damage-independent mechanisms, including phosphorylation, and that PARP-1 plays a role in activation of pro-proliferation signaling pathways (NF-κB, NFAT, HIF-1α) and expression of inflammatory cytokines (2). Previous work from the Bonnet group demonstrated that distal pulmonary arteries and PASMC from patients with PAH have increased DNA damage and increased expression of PARP-1. Indeed, a recent study by Federici and colleagues (5) indicates that baseline levels of DNA damage are intrinsically higher in cells from PAH patients as well as in cells from their unaffected relatives, suggesting that DNA damage may be a genetically determined trait that occurs prior to disease onset. Reactive oxygen species (ROS) have been shown to lead to activation of PARP-1, and the increased DNA damage seen in PAH patients is associated with increased oxidative stress (Fig. 1) (5). Increases in ROS contribute to the stabilization of HIF-1α and HIF-2α, and this provides a possible explanation for the normoxic stabilization of HIF-1α seen in PAH patients. HIF-1 inhibits expression of miR-223 (7), while HIF-2 enhances expression of miR-130/301 (1). Recent studies have demonstrated that DNA damage can alter the expression profile of miRNAs and that miRNAs are involved in the DNA damage response (reviewed in ref. 10). This suggests that DNA damage may be responsible for the altered expression of miR-130/301 and miR-223 seen in PAH patients. The increase in ROS and PARP-1 together activate signaling pathways that promote proliferation and so contribute to the development of PH. The current study by the Bonnet group highlights the role of miR-223 and PARP-1 in PH. Further studies are needed to completely understand the complex relationships among ROS, PARP-1, and miRNAs in order to identify potential biomarkers or therapeutic targets for the treatment of PH.Fig. 1.Proposed role of miRNAs and PARP-1 in the development of pulmonary hypertension. In pulmonary arterial smooth muscle cells, increased levels of ROS result in increased DNA damage and stabilization of HIF-1α and HIF-2α. Increased HIF-1α decreases expression of miR-223, resulting in increased PARP-1. Increased PARP-1 further activates HIF-1α, decreases expression of miR-204, promotes STAT3 and NFAT signaling, and enhances proliferation. Together, activation of these pathways promotes pulmonary vascular remodeling and the development of pulmonary hypertension.Download figureDownload PowerPointDISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the author(s).AUTHOR CONTRIBUTIONSK.A.S. prepared figure; K.A.S. drafted manuscript; K.A.S., J.X.-J.Y., and P.T.S. edited and revised manuscript; K.A.S., J.X.-J.Y., and P.T.S. approved final version of manuscript.REFERENCES1. Bertero T, Lu Y, Annis S, Hale A, Bhat B, Saggar R, Saggar R, Wallace WD, Ross DJ, Vargas SO, Graham BB, Kumar R, Black SM, Fratz S, Fineman JR, West JD, Haley KJ, Waxman AB, Chau BN, Cottrill KA, Chan SY. Systems-level regulation of microRNA networks by miR-130/301 promotes pulmonary hypertension. J Clin Invest 124: 3514–3528, 2014.Crossref | PubMed | ISI | Google Scholar2. Bürkle A, Virág L. Poly(ADP-ribose): PARadigms and PARadoxes. Mol Aspects Med 34: 1046–1065, 2013.Crossref | PubMed | ISI | Google Scholar3. Caruso P, MacLean MR, Khanin R, McClure J, Soon E, Southgate M, MacDonald RA, Greig JA, Robertson KE, Masson R, Denby L, Dempsie Y, Long L, Morrell NW, Baker AH. Dynamic changes in lung microRNA profiles during the development of pulmonary hypertension due to chronic hypoxia and monocrotaline. Arterioscler Thromb Vasc Biol 30: 716–723, 2010.Crossref | PubMed | ISI | Google Scholar4. Courboulin A, Paulin R, Giguere NJ, Saksouk N, Perreault T, Meloche J, Paquet ER, Biardel S, Provencher S, Cote J, Simard MJ, Bonnet S. Role for miR-204 in human pulmonary arterial hypertension. J Exp Med 208: 535–548, 2011.Crossref | PubMed | ISI | Google Scholar5. Federici C, Drake KM, Rigelsky CM, McNelly LN, Meade SL, Comhair SA, Erzurum SC, Aldred MA. Increased mutagen sensitivity and DNA damage in pulmonary arterial hypertension. Am J Respir Crit Care Med 192: 219–228, 2015.Crossref | PubMed | ISI | Google Scholar6. Kim J, Kang Y, Kojima Y, Lighthouse JK, Hu X, Aldred MA, McLean DL, Park H, Comhair SA, Greif DM, Erzurum SC, Chun HJ. An endothelial apelin-FGF link mediated by miR-424 and miR-503 is disrupted in pulmonary arterial hypertension. Nat Med 19: 74–82, 2013.Crossref | PubMed | ISI | Google Scholar7. Meloche J, Le Guen M, Potus F, Vinck J, Ranchoux B, Johnson I, Antigny F, Tremblay E, Breuils-Bonnet S, Perros F, Provencher S, Bonnet S. miR-223 reverses experimental pulmonary arterial hypertension. Am J Physiol Cell Physiol (June 17, 2015). doi: 10.1152/ajpcell.00149.2015.Link | ISI | Google Scholar8. Schlosser K, Taha M, Deng Y, Jiang B, Stewart DJ. Discordant regulation of microRNA between multiple experimental models and human pulmonary hypertension. Chest doi: 10.1378/chest.14–2169. [Epub ahead of print]Crossref | ISI | Google Scholar9. Taïbi F, Metzinger-Le Meuth V, Massy ZA, Metzinger L. miR-223: an inflammatory oncomiR enters the cardiovascular field. Biochim Biophhys Acta 1842: 1001–1009, 2014.Crossref | PubMed | ISI | Google Scholar10. Zhang C, Peng G. Non-coding RNAs: an emerging player in DNA damage response. Mutat Res Rev Mutat Res 763: 202–211, 2015.Crossref | PubMed | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: K. A. Smith, Dept. of Pediatrics, Northwestern Univ., Morton 4-685, 310 E. Superior St., Chicago, IL 60611 (e-mail: [email protected]edu). 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