MicroRNAs and PARP: co-conspirators with ROS in pulmonary hypertension. Focus on "miR-223 reverses experimental pulmonary arterial hypertension".

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, noncoding 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 hypoxiaand 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 miR223 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, hypoxiainducible factor 1 (HIF-1 ) 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 in-