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Idiopathic pulmonary hypertension (IPAH) is a rare disease characterized by a progressive increase in pulmonary vascular resistance leading to heart failure. MicroRNAs (miRNAs) are small noncoding RNAs that control the expression of genes, including some involved in the progression of IPAH, as studied in animals and lung tissue. These molecules circulate freely in the blood and their expression is associated with the progression of different vascular pathologies. Here, we studied the expression profile of circulating miRNAs in 12 well-characterized IPAH patients using microarrays. We found significant changes in 61 miRNAs, of which the expression of miR23a was correlated with the patients' pulmonary function. We also studied the expression profile of circulating messenger RNA (mRNAs) and found that miR23a controlled 17% of the significantly changed mRNA, including PGC1α, which was recently associated with the progression of IPAH. Finally we found that silencing of miR23a resulted in an increase of the expression of PGC1α, as well as in its well-known regulated genes CYC, SOD, NRF2, and HO1. The results point to the utility of circulating miRNA expression as a biomarker of disease progression.

Idiopathic Pulmonary arterial hypertension (IPAH) is characterized by the obstructive remodelling of pulmonary arteries, and a progressive elevation in pulmonary arterial pressure (PAP) with subsequent right-sided heart failure and dead. Hypoxia induces the expression of peroxisome proliferator activated receptor γ coactivator-1α (PGC-1α) which regulates oxidative metabolism and mitochondrial biogenesis. We have analysed the expression of PGC-1α, cytochrome C (CYTC), superoxide dismutase (SOD), the total antioxidant status (TAS) and the activity of glutathione peroxidase (GPX) in blood samples of IPAH patients. Expression of PGC-1α was detected in IPAH patients but not in healthy volunteers. The mRNA levels of SOD were lower in IPAH patients compared to controls (3.93 ± 0.89 fold change). TAS and GPX activity were lower too in patients compared to healthy donors, (0.13 ± 0.027 versus 0.484 ± 0.048 mM and 56.034 ± 10.37 versus 165.46 ± 11.38 nmol/min/mL, resp.). We found a negative correlation between expression levels of PGC-1α and age, PAP and PVR, as well as a positive correlation with CI, PaO(2), mRNA levels of CYTC and SOD, TAS and GPX activity. These results taken together are indicative of the possible role of PGC-1α as a potential biomarker of the progression of IPAH.

1. The present study has evaluated the effect of two phenanthrene alkaloids, uvariopsine and stephenanthrine, on angiotensin II (Ang-II)-induced leukocyte-endothelial cell interactions in vivo and the mechanisms involved in their activity. Intravital microscopy within the rat mesenteric microcirculation was used. 2. A 60 min superfusion with 1 nm Ang-II induced a significant increase in the leukocyte-endothelial cell interactions that were completely inhibited by 1 microm uvariopsine cosuperfusion. A lower dose of 0.1 microm significantly reduced Ang-II-induced leukocyte adhesion by 75%. 3. When Ang-II was cosuperfused with 1 and 0.1 microm stephenanthrine, Ang-II-induced leukocyte responses were significantly diminished. A lower dose of 0.01 microm only affected Ang-II-induced leukocyte adhesion. 4. Both alkaloids inhibited Ang-II-induced endothelial P-selectin upregulation and the generation of reactive oxygen species (ROS) in endothelial cells stimulated with Ang-II, in fMLP-stimulated human neutrophils (PMNs) and in the hypoxanthine-xanthine oxidase system. However, cyclic AMP levels in PMNs stimulated with fMLP were not affected. 5. Uvariopsine and stephenanthrine inhibited PAF-induced elevations in intracellular calcium levels in PMNs (IC50 values: 15.1 and 6.1 microm respectively) and blocked the binding of [3H]PAF to these leukocytes. They also reduced PAF-induced increases in intracellular levels of superoxide anion and hydrogen peroxide. 6. In conclusion, stephenanthrine and uvariopsine are potent inhibitors of Ang-II-induced leukocyte accumulation in vivo. This effect appears to be mediated through ROS scavenging activity and blockade of PAF receptor. Thus, they have potential therapeutic interest for the control of leukocyte recruitment that occurs in cardiovascular disease states in which Ang-II is involved.