Bisserier, M;
Katz, MG;
Bueno-Beti, C;
Brojakowska, A;
Zhang, S;
Gubara, S;
Kohlbrenner, E;
Fazal, S;
Fargnoli, A;
Dorfmuller, P;
et al.
Bisserier, M; Katz, MG; Bueno-Beti, C; Brojakowska, A; Zhang, S; Gubara, S; Kohlbrenner, E; Fazal, S; Fargnoli, A; Dorfmuller, P; Humbert, M; Hata, A; Goukassian, DA; Sassi, Y; Hadri, L
(2021)
Combination Therapy with STAT3 Inhibitor Enhances SERCA2a-Induced BMPR2 Expression and Inhibits Pulmonary Arterial Hypertension.
Int J Mol Sci, 22 (17).
p. 9105.
ISSN 1422-0067
https://doi.org/10.3390/ijms22179105
SGUL Authors: Bueno Beti, Carlos
|
PDF
Published Version
Available under License Creative Commons Attribution. Download (6MB) | Preview |
|
![]() |
Archive (ZIP) (Supplementary Material)
Published Version
Available under License Creative Commons Attribution. Download (1MB) |
Abstract
Pulmonary arterial hypertension (PAH) is a devastating lung disease characterized by the progressive obstruction of the distal pulmonary arteries (PA). Structural and functional alteration of pulmonary artery smooth muscle cells (PASMC) and endothelial cells (PAEC) contributes to PA wall remodeling and vascular resistance, which may lead to maladaptive right ventricular (RV) failure and, ultimately, death. Here, we found that decreased expression of sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) in the lung samples of PAH patients was associated with the down-regulation of bone morphogenetic protein receptor type 2 (BMPR2) and the activation of signal transducer and activator of transcription 3 (STAT3). Our results showed that the antiproliferative properties of SERCA2a are mediated through the STAT3/BMPR2 pathway. At the molecular level, transcriptome analysis of PASMCs co-overexpressing SERCA2a and BMPR2 identified STAT3 amongst the most highly regulated transcription factors. Using a specific siRNA and a potent pharmacological STAT3 inhibitor (STAT3i, HJC0152), we found that SERCA2a potentiated BMPR2 expression by repressing STAT3 activity in PASMCs and PAECs. In vivo, we used a validated and efficient model of severe PAH induced by unilateral left pneumonectomy combined with monocrotaline (PNT/MCT) to further evaluate the therapeutic potential of single and combination therapies using adeno-associated virus (AAV) technology and a STAT3i. We found that intratracheal delivery of AAV1 encoding SERCA2 or BMPR2 alone or STAT3i was sufficient to reduce the mean PA pressure and vascular remodeling while improving RV systolic pressures, RV ejection fraction, and cardiac remodeling. Interestingly, we found that combined therapy of AAV1.hSERCA2a with AAV1.hBMPR2 or STAT3i enhanced the beneficial effects of SERCA2a. Finally, we used cardiac magnetic resonance imaging to measure RV function and found that therapies using AAV1.hSERCA2a alone or combined with STAT3i significantly inhibited RV structural and functional changes in PNT/MCT-induced PAH. In conclusion, our study demonstrated that combination therapies using SERCA2a gene transfer with a STAT3 inhibitor could represent a new promising therapeutic alternative to inhibit PAH and to restore BMPR2 expression by limiting STAT3 activity.
Item Type: | Article | |||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Additional Information: | Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). | |||||||||||||||
Keywords: | BMPR2, SERCA2a, STAT3, gene therapy, pulmonary arterial hypertension, right heart failure, 0399 Other Chemical Sciences, 0604 Genetics, 0699 Other Biological Sciences, Chemical Physics | |||||||||||||||
SGUL Research Institute / Research Centre: | Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) | |||||||||||||||
Journal or Publication Title: | Int J Mol Sci | |||||||||||||||
ISSN: | 1422-0067 | |||||||||||||||
Language: | eng | |||||||||||||||
Dates: |
|
|||||||||||||||
Publisher License: | Creative Commons: Attribution 4.0 | |||||||||||||||
Projects: |
|
|||||||||||||||
PubMed ID: | 34502015 | |||||||||||||||
Go to PubMed abstract | ||||||||||||||||
URI: | https://openaccess.sgul.ac.uk/id/eprint/113666 | |||||||||||||||
Publisher's version: | https://doi.org/10.3390/ijms22179105 |
Statistics
Actions (login required)
![]() |
Edit Item |