Kynurenine-PARP 1 link mediated by microRNA 210 may be dysregulated in pulmonary hypertension

Abstract

Abstract Background The aims of the present study were to determine the alterations in mRNA and miR expressions and their role in signaling pathways, to correlate their levels with the severity of PH, and to investigate the relationship between those alterations and serum levels of apelin, kynurenine, and endocan in PH. Methods The study included 32 treatment-naive patients with precapillary PH and 55 controls. All subjects underwent RHC. Total RNA was isolated and cDNAs for mRNA and miR were synthesized. mRNA expressions of HIF-1α, HIF-2α, STAT 3, FGF-2, FGFR-1, PARP 1 and miR expressions of miR-210, miR-130a, miR-424, miR-204, and miR-223 were determined. Concentrations of kynurenine, apelin, and endocan were analyzed. Results HIF-2α, STAT 3, and FGF-2 were increased; miR-210 and miR-130a were increased; miR-223 and miR-204 were decreased. Apelin and kynurenine concentrations were decreased. There were positive correlations: HIF-2α-miR-424: r=0.474, p=0.011; APLN-miR-424: r=0.385, p=0.030; kynurenine-miR-210: r=0.551, p=0.004; STAT 3- PVR: r=0.478, p=0.006; miR-210- RAP: r=0.536, p=0.07; kynurenine-RAP: r=0.409, p=0.022. There were negative correlations: PARP 1-miR-210: r=−0.561, p=0.007; PARP 1- RAP: r=−0.424, p=0.27. miR-130a (OR= 1.257, p=0.016) and APLN (OR= 0.223, p=0.004) were independent risk factors for PH. Conclusions We report: 1) novel relationship between the kynurenine and PARP 1 signaling pathways that could be mediated by miR-210, 2) relationship between the apelin and HIF-2α signaling pathways that could be mediated by miR-424, 3) reduced levels of apelin and elevated levels of miR-130a are associated with PH, 4) elevated levels of STAT 3, miR-210, and kynurenine, and reduced levels of PARP 1 correlate with more severe hemodynamics. Funding Acknowledgement Type of funding source: Other. Main funding source(s): Pamukkale University Scientific Research Projects Coordination Unit