Next Article in Journal
Spatiotemporal Changes in Xylan-1/Xyloglucan and Xyloglucan Xyloglucosyl Transferase (XTH-Xet5) as a Step-In of Ultrastructural Cell Wall Remodelling in Potato–Potato Virus Y (PVYNTN) Hypersensitive and Susceptible Reaction
Next Article in Special Issue
Prostanoid EP2 Receptors Are Up-Regulated in Human Pulmonary Arterial Hypertension: A Key Anti-Proliferative Target for Treprostinil in Smooth Muscle Cells
Previous Article in Journal
Differences in Functional Expression of Connexin43 and NaV1.5 by Pan- and Class-Selective Histone Deacetylase Inhibition in Heart
Previous Article in Special Issue
Myeloid-Derived Suppressor Cells and Pulmonary Hypertension
Article Menu

Export Article

Open AccessArticle
Int. J. Mol. Sci. 2018, 19(8), 2289; https://doi.org/10.3390/ijms19082289

Factors Associated with Heritable Pulmonary Arterial Hypertension Exert Convergent Actions on the miR-130/301-Vascular Matrix Feedback Loop

1
Université Côte d’Azur, CNRS UMR7284, INSERM U1081, IRCAN, Nice 06100, France
2
Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
*
Authors to whom correspondence should be addressed.
Received: 17 July 2018 / Revised: 31 July 2018 / Accepted: 1 August 2018 / Published: 4 August 2018
(This article belongs to the Special Issue Molecular Research on Pulmonary Hypertension)
View Full-Text   |   Download PDF [20593 KB, uploaded 4 August 2018]   |  

Abstract

Pulmonary arterial hypertension (PAH) is characterized by occlusion of lung arterioles, leading to marked increases in pulmonary vascular resistance. Although heritable forms of PAH are known to be driven by genetic mutations that share some commonality of function, the extent to which these effectors converge to regulate shared processes in this disease is unknown. We have causally connected extracellular matrix (ECM) remodeling and mechanotransduction to the miR-130/301 family in a feedback loop that drives vascular activation and downstream PAH. However, the molecular interconnections between factors genetically associated with PAH and this mechano-driven feedback loop remain undefined. We performed systematic manipulation of matrix stiffness, the miR-130/301 family, and factors genetically associated with PAH in primary human pulmonary arterial cells and assessed downstream and reciprocal consequences on their expression. We found that a network of factors linked to heritable PAH converges upon the matrix stiffening-miR-130/301-PPARγ-LRP8 axis in order to remodel the ECM. Furthermore, we leveraged a computational network biology approach to predict a number of additional molecular circuits functionally linking this axis to the ECM. These results demonstrate that multiple genes associated with heritable PAH converge to control the miR-130/301 circuit, triggering a self-amplifying feedback process central to pulmonary vascular stiffening and disease. View Full-Text
Keywords: heritable pulmonary hypertension; pulmonary arterial hypertension; genetic predisposition; microRNA; extracellular matrix; fibrosis heritable pulmonary hypertension; pulmonary arterial hypertension; genetic predisposition; microRNA; extracellular matrix; fibrosis
Figures

Figure 1

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

Supplementary material

SciFeed

Share & Cite This Article

MDPI and ACS Style

Bertero, T.; Handen, A.L.; Chan, S.Y. Factors Associated with Heritable Pulmonary Arterial Hypertension Exert Convergent Actions on the miR-130/301-Vascular Matrix Feedback Loop. Int. J. Mol. Sci. 2018, 19, 2289.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top