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Volume 22
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10.3390/ijms22179105
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Article

Combination Therapy with STAT3 Inhibitor Enhances SERCA2a-Induced BMPR2 Expression and Inhibits Pulmonary Arterial Hypertension

by
Malik Bisserier
1,*,
Michael G. Katz
1,
Carlos Bueno-Beti
1,
Agnieszka Brojakowska
1,
Shihong Zhang
1,
Sarah Gubara
1,
Erik Kohlbrenner
1,
Shahood Fazal
1,
Anthony Fargnoli
1,
Peter Dorfmuller
2,
Marc Humbert
3,
Akiko Hata
4,
David A. Goukassian
1,
Yassine Sassi
1 and
Lahouaria Hadri
1,*
1
Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
2
Department of Pathology, University Hospital of Giessen and Marburg (UKGM), Langhansstrasse 10, 35392 Giessen, Germany
3
Assistance Publique-Hôpitaux de Paris (AP-HP), Service de Pneumologie et Soins Intensifs Respiratoires, Centre de Référence de l’Hypertension Pulmonaire, Hôpital Bicêtre, 94270 Le Kremlin-Bicêtre, France
4
Cardiovascular Research Institute, University of California, San Francisco, CA 94143, USA
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(17), 9105; https://doi.org/10.3390/ijms22179105
Submission received: 3 August 2021 / Accepted: 16 August 2021 / Published: 24 August 2021
(This article belongs to the Section Molecular Biology)
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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.
Keywords: gene therapy; pulmonary arterial hypertension; right heart failure; BMPR2; SERCA2a; STAT3 gene therapy; pulmonary arterial hypertension; right heart failure; BMPR2; SERCA2a; STAT3
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MDPI and ACS Style

Bisserier, M.; Katz, M.G.; Bueno-Beti, C.; Brojakowska, A.; Zhang, S.; Gubara, S.; Kohlbrenner, E.; Fazal, S.; Fargnoli, A.; Dorfmuller, P.; et al. Combination Therapy with STAT3 Inhibitor Enhances SERCA2a-Induced BMPR2 Expression and Inhibits Pulmonary Arterial Hypertension. Int. J. Mol. Sci. 2021, 22, 9105. https://doi.org/10.3390/ijms22179105

AMA Style

Bisserier M, Katz MG, Bueno-Beti C, Brojakowska A, Zhang S, Gubara S, Kohlbrenner E, Fazal S, Fargnoli A, Dorfmuller P, et al. Combination Therapy with STAT3 Inhibitor Enhances SERCA2a-Induced BMPR2 Expression and Inhibits Pulmonary Arterial Hypertension. International Journal of Molecular Sciences. 2021; 22(17):9105. https://doi.org/10.3390/ijms22179105

Chicago/Turabian Style

Bisserier, Malik, Michael G. Katz, Carlos Bueno-Beti, Agnieszka Brojakowska, Shihong Zhang, Sarah Gubara, Erik Kohlbrenner, Shahood Fazal, Anthony Fargnoli, Peter Dorfmuller, and et al. 2021. "Combination Therapy with STAT3 Inhibitor Enhances SERCA2a-Induced BMPR2 Expression and Inhibits Pulmonary Arterial Hypertension" International Journal of Molecular Sciences 22, no. 17: 9105. https://doi.org/10.3390/ijms22179105

APA Style

Bisserier, M., Katz, M. G., Bueno-Beti, C., Brojakowska, A., Zhang, S., Gubara, S., Kohlbrenner, E., Fazal, S., Fargnoli, A., Dorfmuller, P., Humbert, M., Hata, A., Goukassian, D. A., Sassi, Y., & Hadri, L. (2021). Combination Therapy with STAT3 Inhibitor Enhances SERCA2a-Induced BMPR2 Expression and Inhibits Pulmonary Arterial Hypertension. International Journal of Molecular Sciences, 22(17), 9105. https://doi.org/10.3390/ijms22179105

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