Inhibition of the prolyl isomerase Pin1 improves endothelial function and attenuates vascular remodelling in pulmonary hypertension by inhibiting TGF-β signalling

Kondababu Kurakula; Quint A.J. Hagdorn; Diederik E. van der Feen; Anton Vonk Noordegraaf; Peter ten Dijke; Rudolf A. de Boer; Harm Jan Bogaard; Marie José Goumans; Rolf M.F. Berger

doi:10.1007/s10456-021-09812-7

Inhibition of the prolyl isomerase Pin1 improves endothelial function and attenuates vascular remodelling in pulmonary hypertension by inhibiting TGF-β signalling

Kondababu Kurakula^*
, Quint A.J. Hagdorn
, Diederik E. van der Feen
, Anton Vonk Noordegraaf
, Peter ten Dijke
, Rudolf A. de Boer
, Harm Jan Bogaard
, Marie José Goumans^*
, Rolf M.F. Berger

^*Corresponding author for this work

Leiden University Medical Centre
University of Groningen
Vrije Universiteit Amsterdam
University Medical Centre Groningen

Research output: Contribution to journal › Article › Academic › peer-review

15 Citations (Scopus)

Abstract

Pulmonary arterial hypertension (PAH) is a devastating disease, characterized by obstructive pulmonary vascular remodelling ultimately leading to right ventricular (RV) failure and death. Disturbed transforming growth factor-β (TGF-β)/bone morphogenetic protein (BMP) signalling, endothelial cell dysfunction, increased proliferation of smooth muscle cells and fibroblasts, and inflammation contribute to this abnormal remodelling. Peptidyl-prolyl isomerase Pin1 has been identified as a critical driver of proliferation and inflammation in vascular cells, but its role in the disturbed TGF-β/BMP signalling, endothelial cell dysfunction, and vascular remodelling in PAH is unknown. Here, we report that Pin1 expression is increased in cultured pulmonary microvascular endothelial cells (MVECs) and lung tissue of PAH patients. Pin1 inhibitor, juglone significantly decreased TGF-β signalling, increased BMP signalling, normalized their hyper-proliferative, and inflammatory phenotype. Juglone treatment reversed vascular remodelling through reducing TGF-β signalling in monocrotaline + shunt-PAH rat model. Juglone treatment decreased Fulton index, but did not affect or harm cardiac function and remodelling in rats with RV pressure load induced by pulmonary artery banding. Our study demonstrates that inhibition of Pin1 reversed the PAH phenotype in PAH MVECs in vitro and in PAH rats in vivo, potentially through modulation of TGF-β/BMP signalling pathways. Selective inhibition of Pin1 could be a novel therapeutic option for the treatment of PAH.

Original language	English
Pages (from-to)	99-112
Number of pages	14
Journal	Angiogenesis
Volume	25
Issue number	1
DOIs	https://doi.org/10.1007/s10456-021-09812-7
Publication status	Published - Feb 2022
Externally published	Yes

Bibliographical note

Funding Information:
We thank Martijn Rabelink (Leiden university medical center, Leiden, The Netherlands) for providing shRNAs targeting Pin1, Robert Szulcek and X. Pan (Amsterdam university medical center, Amsterdam, The Netherlands) for MVECs isolation and Tiago Ferraz, Kirsten Lodder and Nora Carubelli for their help with in vitro experiments.

Funding Information:
We acknowledge support from the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centers, the Netherlands Organization for Health Research and Development, and the Royal Netherlands Academy of Sciences Grant 2012–2008 and 2018–2023 awarded to the Phaedra consortium ( http://www.phaedraresearch.nl ). We also acknowledge support from the Stichting Hartekind and the Sebald fund and support for KK by the Dutch lung foundation grant number-5.2.17.198J0, and Leiden University Foundation grant- W18378-2-32.

Publisher Copyright:
© 2021, The Author(s).

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10.1007/s10456-021-09812-7

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Kurakula, K., Hagdorn, Q. A. J., van der Feen, D. E., Vonk Noordegraaf, A., ten Dijke, P., de Boer, R. A., Bogaard, H. J., Goumans, M. J., & Berger, R. M. F. (2022). Inhibition of the prolyl isomerase Pin1 improves endothelial function and attenuates vascular remodelling in pulmonary hypertension by inhibiting TGF-β signalling. Angiogenesis, 25(1), 99-112. https://doi.org/10.1007/s10456-021-09812-7

@article{829c17113ca1483aa4e0eb9feccb6a63,

title = "Inhibition of the prolyl isomerase Pin1 improves endothelial function and attenuates vascular remodelling in pulmonary hypertension by inhibiting TGF-β signalling",

abstract = "Pulmonary arterial hypertension (PAH) is a devastating disease, characterized by obstructive pulmonary vascular remodelling ultimately leading to right ventricular (RV) failure and death. Disturbed transforming growth factor-β (TGF-β)/bone morphogenetic protein (BMP) signalling, endothelial cell dysfunction, increased proliferation of smooth muscle cells and fibroblasts, and inflammation contribute to this abnormal remodelling. Peptidyl-prolyl isomerase Pin1 has been identified as a critical driver of proliferation and inflammation in vascular cells, but its role in the disturbed TGF-β/BMP signalling, endothelial cell dysfunction, and vascular remodelling in PAH is unknown. Here, we report that Pin1 expression is increased in cultured pulmonary microvascular endothelial cells (MVECs) and lung tissue of PAH patients. Pin1 inhibitor, juglone significantly decreased TGF-β signalling, increased BMP signalling, normalized their hyper-proliferative, and inflammatory phenotype. Juglone treatment reversed vascular remodelling through reducing TGF-β signalling in monocrotaline + shunt-PAH rat model. Juglone treatment decreased Fulton index, but did not affect or harm cardiac function and remodelling in rats with RV pressure load induced by pulmonary artery banding. Our study demonstrates that inhibition of Pin1 reversed the PAH phenotype in PAH MVECs in vitro and in PAH rats in vivo, potentially through modulation of TGF-β/BMP signalling pathways. Selective inhibition of Pin1 could be a novel therapeutic option for the treatment of PAH.",

author = "Kondababu Kurakula and Hagdorn, \{Quint A.J.\} and \{van der Feen\}, \{Diederik E.\} and \{Vonk Noordegraaf\}, Anton and \{ten Dijke\}, Peter and \{de Boer\}, \{Rudolf A.\} and Bogaard, \{Harm Jan\} and Goumans, \{Marie Jos{\'e}\} and Berger, \{Rolf M.F.\}",

note = "Funding Information: We thank Martijn Rabelink (Leiden university medical center, Leiden, The Netherlands) for providing shRNAs targeting Pin1, Robert Szulcek and X. Pan (Amsterdam university medical center, Amsterdam, The Netherlands) for MVECs isolation and Tiago Ferraz, Kirsten Lodder and Nora Carubelli for their help with in vitro experiments. Funding Information: We acknowledge support from the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centers, the Netherlands Organization for Health Research and Development, and the Royal Netherlands Academy of Sciences Grant 2012–2008 and 2018–2023 awarded to the Phaedra consortium ( http://www.phaedraresearch.nl ). We also acknowledge support from the Stichting Hartekind and the Sebald fund and support for KK by the Dutch lung foundation grant number-5.2.17.198J0, and Leiden University Foundation grant- W18378-2-32. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2022",

month = feb,

doi = "10.1007/s10456-021-09812-7",

language = "English",

volume = "25",

pages = "99--112",

journal = "Angiogenesis",

issn = "0969-6970",

publisher = "Springer Science+Business Media",

number = "1",

}

Kurakula, K, Hagdorn, QAJ, van der Feen, DE, Vonk Noordegraaf, A, ten Dijke, P, de Boer, RA, Bogaard, HJ, Goumans, MJ & Berger, RMF 2022, 'Inhibition of the prolyl isomerase Pin1 improves endothelial function and attenuates vascular remodelling in pulmonary hypertension by inhibiting TGF-β signalling', Angiogenesis, vol. 25, no. 1, pp. 99-112. https://doi.org/10.1007/s10456-021-09812-7

Inhibition of the prolyl isomerase Pin1 improves endothelial function and attenuates vascular remodelling in pulmonary hypertension by inhibiting TGF-β signalling. / Kurakula, Kondababu; Hagdorn, Quint A.J.; van der Feen, Diederik E. et al.
In: Angiogenesis, Vol. 25, No. 1, 02.2022, p. 99-112.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Inhibition of the prolyl isomerase Pin1 improves endothelial function and attenuates vascular remodelling in pulmonary hypertension by inhibiting TGF-β signalling

AU - Kurakula, Kondababu

AU - Hagdorn, Quint A.J.

AU - van der Feen, Diederik E.

AU - Vonk Noordegraaf, Anton

AU - ten Dijke, Peter

AU - de Boer, Rudolf A.

AU - Bogaard, Harm Jan

AU - Goumans, Marie José

AU - Berger, Rolf M.F.

N1 - Funding Information: We thank Martijn Rabelink (Leiden university medical center, Leiden, The Netherlands) for providing shRNAs targeting Pin1, Robert Szulcek and X. Pan (Amsterdam university medical center, Amsterdam, The Netherlands) for MVECs isolation and Tiago Ferraz, Kirsten Lodder and Nora Carubelli for their help with in vitro experiments. Funding Information: We acknowledge support from the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centers, the Netherlands Organization for Health Research and Development, and the Royal Netherlands Academy of Sciences Grant 2012–2008 and 2018–2023 awarded to the Phaedra consortium ( http://www.phaedraresearch.nl ). We also acknowledge support from the Stichting Hartekind and the Sebald fund and support for KK by the Dutch lung foundation grant number-5.2.17.198J0, and Leiden University Foundation grant- W18378-2-32. Publisher Copyright: © 2021, The Author(s).

PY - 2022/2

Y1 - 2022/2

N2 - Pulmonary arterial hypertension (PAH) is a devastating disease, characterized by obstructive pulmonary vascular remodelling ultimately leading to right ventricular (RV) failure and death. Disturbed transforming growth factor-β (TGF-β)/bone morphogenetic protein (BMP) signalling, endothelial cell dysfunction, increased proliferation of smooth muscle cells and fibroblasts, and inflammation contribute to this abnormal remodelling. Peptidyl-prolyl isomerase Pin1 has been identified as a critical driver of proliferation and inflammation in vascular cells, but its role in the disturbed TGF-β/BMP signalling, endothelial cell dysfunction, and vascular remodelling in PAH is unknown. Here, we report that Pin1 expression is increased in cultured pulmonary microvascular endothelial cells (MVECs) and lung tissue of PAH patients. Pin1 inhibitor, juglone significantly decreased TGF-β signalling, increased BMP signalling, normalized their hyper-proliferative, and inflammatory phenotype. Juglone treatment reversed vascular remodelling through reducing TGF-β signalling in monocrotaline + shunt-PAH rat model. Juglone treatment decreased Fulton index, but did not affect or harm cardiac function and remodelling in rats with RV pressure load induced by pulmonary artery banding. Our study demonstrates that inhibition of Pin1 reversed the PAH phenotype in PAH MVECs in vitro and in PAH rats in vivo, potentially through modulation of TGF-β/BMP signalling pathways. Selective inhibition of Pin1 could be a novel therapeutic option for the treatment of PAH.

AB - Pulmonary arterial hypertension (PAH) is a devastating disease, characterized by obstructive pulmonary vascular remodelling ultimately leading to right ventricular (RV) failure and death. Disturbed transforming growth factor-β (TGF-β)/bone morphogenetic protein (BMP) signalling, endothelial cell dysfunction, increased proliferation of smooth muscle cells and fibroblasts, and inflammation contribute to this abnormal remodelling. Peptidyl-prolyl isomerase Pin1 has been identified as a critical driver of proliferation and inflammation in vascular cells, but its role in the disturbed TGF-β/BMP signalling, endothelial cell dysfunction, and vascular remodelling in PAH is unknown. Here, we report that Pin1 expression is increased in cultured pulmonary microvascular endothelial cells (MVECs) and lung tissue of PAH patients. Pin1 inhibitor, juglone significantly decreased TGF-β signalling, increased BMP signalling, normalized their hyper-proliferative, and inflammatory phenotype. Juglone treatment reversed vascular remodelling through reducing TGF-β signalling in monocrotaline + shunt-PAH rat model. Juglone treatment decreased Fulton index, but did not affect or harm cardiac function and remodelling in rats with RV pressure load induced by pulmonary artery banding. Our study demonstrates that inhibition of Pin1 reversed the PAH phenotype in PAH MVECs in vitro and in PAH rats in vivo, potentially through modulation of TGF-β/BMP signalling pathways. Selective inhibition of Pin1 could be a novel therapeutic option for the treatment of PAH.

UR - https://www.scopus.com/pages/publications/85112246720

U2 - 10.1007/s10456-021-09812-7

DO - 10.1007/s10456-021-09812-7

M3 - Article

C2 - 34379232

AN - SCOPUS:85112246720

SN - 0969-6970

VL - 25

SP - 99

EP - 112

JO - Angiogenesis

JF - Angiogenesis

IS - 1

ER -

Inhibition of the prolyl isomerase Pin1 improves endothelial function and attenuates vascular remodelling in pulmonary hypertension by inhibiting TGF-β signalling

Abstract

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