Kynurenine-PARP-1 Link Mediated by MicroRNA 210 May Be Dysregulated in Pulmonary Hypertension
Alperen Emre Akgün1, Yalın Tolga Yaylalı2, Mücahit Seçme3
1Department of Cardiology, Uşak Training and Research Hospital, Uşak, Turkey.
Background:
Dysregulation of microRNAs is associated with pulmonary hyperten-sion. The present study aimed to determine the alterations in microRNA and microRNA expressions and their role in signaling pathways and investigate the relationship with serum levels of apelin, kynurenine, and endocan in pulmonary hypertension.
Methods:
The study design was prospective and single-centered. The study included 32 consecutive treatment-naive patients with precapillary pulmonary hypertension and 55 age and sex-matched healthy controls. All subjects underwent right heart catheter-ization. mRNA expressions of hypoxia-inducible factor-1 alpha, hypoxia-inducible fac-tor-2 alpha, signal transducer and activator of transcription-3, fibroblast growth factor-2, fibroblast growth factor receptor-1, and poly-ADP-ribose polymerase-1 and microRNA expressions of miRNA-210, miRNA-130a, miRNA-424, miRNA-204, and miRNA-223 weredetermined by RT-PCR. Concentrations of kynurenine, apelin, and endocan were ana-lyzed by ELISA.
Results:
mRNA expressions of hypoxia-inducible factor-2 alpha, signal transducer and activator of transcription-33, and FGF-2 were increased; miRNA-210 and miRNA-130a were increased; miRNA-223 and miRNA-204 were decreased in pulmonary hyperten-sion. Apelin and kynurenine concentrations were decreased in pulmonary hypertension. There were positive correlations: hypoxia-inducible factor-2 alpha-miRNA-424, Apelin- miRNA-424, kynurenine-miRNA-210, signal transducer and activator of transcription- 3-PVR, miRNA-210-right atrial pressure, and kynurenine-right atrial pressure. There were negative correlations: poly-ADP-ribose polymerase-1-miRNA-210 and poly-ADP-ribose polymerase-1-right atrial pressure. On multiple logistic regression analyses, miRNA-130a and Apelin were independent risk factors for PH.
Conclusions:
We report a novel relationship between the kynurenine and poly-ADP- ribose polymerase-1 signaling pathways that could be mediated by miRNA-210. We also report a connection between the Apelin and hypoxia-inducible factor-2 alpha signaling pathways that could be mediated by miRNA-424. Reduced levels of Apelin and elevated levels of miRNA-130a are associated with pulmonary hypertension. We also find that ele-vated levels of signal transducer and activator of transcription-3, miRNA-210, and kyn-urenine and reduced levels of poly-ADP-ribose polymerase-1 correlate with more severe hemodynamics.
Insights
MicroRNA-130a and Apelin are key risk factors for pulmonary hypertension (PH). Their dysregulation, along with altered kynurenine and poly-ADP-ribose polymerase-1 pathways, impacts PH severity and hemodynamics.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Biochemistry
Background:
- MicroRNA (miRNA) dysregulation is implicated in the pathogenesis of pulmonary hypertension (PH).
- Understanding miRNA alterations and their associated signaling pathways is crucial for PH research.
- Serum biomarkers like apelin, kynurenine, and endocan may provide insights into PH mechanisms.
Purpose of the Study:
- To investigate alterations in specific microRNA and mRNA expressions in patients with precapillary pulmonary hypertension.
- To explore the role of these molecular changes in relevant signaling pathways.
- To examine the relationship between these molecular markers and serum levels of apelin, kynurenine, and endocan in PH.
Main Methods:
- Prospective, single-center study involving 32 treatment-naive PH patients and 55 healthy controls.
- Right heart catheterization performed on all subjects.
- RT-PCR used to quantify mRNA (HIF-1α, HIF-2α, STAT3, FGF2, FGFR1, PARP-1) and miRNA (miRNA-210, miRNA-130a, miRNA-424, miRNA-204, miRNA-223) expressions.
- ELISA used to measure serum concentrations of kynurenine, apelin, and endocan.
Main Results:
- Elevated mRNA expressions of HIF-2α, STAT3, and FGF-2; increased miRNA-210 and miRNA-130a; decreased miRNA-223 and miRNA-204 observed in PH patients.
- Reduced serum levels of apelin and kynurenine found in PH.
- Positive correlations identified between HIF-2α/miRNA-424, Apelin/miRNA-424, kynurenine/miRNA-210, STAT3/PVR, miRNA-210/right atrial pressure, and kynurenine/right atrial pressure.
- Negative correlations noted between PARP-1/miRNA-210 and PARP-1/right atrial pressure.
- miRNA-130a and Apelin identified as independent risk factors for PH via logistic regression.
Conclusions:
- A novel link between kynurenine and PARP-1 signaling, potentially mediated by miRNA-210, is reported.
- A connection between Apelin and HIF-2α signaling, possibly mediated by miRNA-424, is suggested.
- Reduced Apelin and elevated miRNA-130a are associated with pulmonary hypertension.
- Increased STAT3, miRNA-210, kynurenine, and decreased PARP-1 correlate with more severe hemodynamics in PH.
Related Concept Videos
01:30Pulmonary Hypertension: Classification and Pathogenesis
There are various classifications for PH, each relating to different underlying causes and also...
01:22MicroRNAs
01:27Transducer Mechanism: Enzyme-Linked Receptors
Major types that are helpful drug targets include:
01:18Treatment for Pulmonary Arterial Hypertension: Endothelin Receptor Antagonists
ETs are synthesized through a complex sequence of enzymatic steps, primarily involving an enzyme referred to as endothelin-converting enzyme...
01:26Treatment for Pulmonary Arterial Hypertension: Receptor Tyrosine Kinase Inhibitors and Calcium Channel Blockers
TKIs, such as imatinib (Gleevec), are particularly effective in tackling the growth and mitogenic factors that become upregulated in PAH patients. These factors contribute to the...
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...