Galectin-3 is expressed in vascular smooth muscle cells and promotes pulmonary hypertension through changes in proliferation, apoptosis, and fibrosis

Scott A. Barman, Xueyi Li, Stephen Haigh, Dmitry Kondrikov, Keyvan Mahboubi, Zsuzsanna Bordan, David W. Stepp, Jiliang Zhou, Yusi Wang, Daniel S. Weintraub, Peter Traber, William Snider, Danny Jonigk, Jennifer Sullivan, G. Ryan Crislip, Joshua T. Butcher, Jennifer Thompson, Yunchao Su, Feng Chen, David J.R. Fulton

Research output: Contribution to journalArticle

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Abstract

A defining characteristic of pulmonary hypertension (PH) is the extensive remodeling of pulmonary arteries (PAs), which results in progressive increases in vascular resistance and stiffness and eventual failure of the right ventricle. There is no cure for PH and identification of novel molecular mechanisms that underlie increased proliferation, reduced apoptosis, and excessive extracellular matrix production in pulmonary artery smooth muscle cells (PASMCs) is a vital objective. Galectin-3 (Gal-3) is a chimeric lectin and potent driver of many aspects of fibrosis, but its role in regulating PASMC behavior in PH remains poorly understood. Herein, we evaluated the importance of increased Gal-3 expression and signaling on PA vascular remodeling and cardiopulmonary function in experimental models of PH. Gal-3 expression was quantified by qRT-PCR, immunoblotting, and immunofluorescence imaging, and its functional role was assessed by specific Gal-3 inhibitors and CRISPR/Cas9-mediated knockout of Gal-3 in the rat. In rat models of PH, we observed increased Gal-3 expression in PASMCs, which stimulated migration and resistance to apoptosis, whereas silencing or genetic deletion reduced cellular migration and PA fibrosis and increased apoptosis. Gal-3 inhibitors attenuated and reversed PA remodeling and fibrosis, as well as hemodynamic indices in monocrotaline (MCT)-treated rats in vivo. These results were supported by genetic deletion of Gal-3 in both MCT and Sugen Hypoxia rat models. In conclusion, our results suggest that elevated Gal-3 levels contribute to inappropriate PA remodeling in PH by enhancing multiple profibrotic mechanisms. Therapeutic strategies targeting Gal-3 may be of benefit in the treatment of PH.

Original languageEnglish (US)
Pages (from-to)L784-L797
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume316
Issue number5
DOIs
StatePublished - May 2019

Fingerprint

Galectin 3
Vascular Smooth Muscle
Pulmonary Hypertension
Smooth Muscle Myocytes
Fibrosis
Pulmonary Artery
Apoptosis
Monocrotaline
Pulmonary Fibrosis
Clustered Regularly Interspaced Short Palindromic Repeats
Vascular Stiffness
Immunoblotting
Lectins
Vascular Resistance
Heart Ventricles
Fluorescent Antibody Technique
Extracellular Matrix
Theoretical Models
Hemodynamics

Keywords

  • Cell migration
  • Fibrosis
  • Galectin-3
  • Knockout rat
  • Pulmonary hypertension
  • Vascular smooth muscle

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

Cite this

Galectin-3 is expressed in vascular smooth muscle cells and promotes pulmonary hypertension through changes in proliferation, apoptosis, and fibrosis. / Barman, Scott A.; Li, Xueyi; Haigh, Stephen; Kondrikov, Dmitry; Mahboubi, Keyvan; Bordan, Zsuzsanna; Stepp, David W.; Zhou, Jiliang; Wang, Yusi; Weintraub, Daniel S.; Traber, Peter; Snider, William; Jonigk, Danny; Sullivan, Jennifer; Ryan Crislip, G.; Butcher, Joshua T.; Thompson, Jennifer; Su, Yunchao; Chen, Feng; Fulton, David J.R.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 316, No. 5, 05.2019, p. L784-L797.

Research output: Contribution to journalArticle

Barman, Scott A. ; Li, Xueyi ; Haigh, Stephen ; Kondrikov, Dmitry ; Mahboubi, Keyvan ; Bordan, Zsuzsanna ; Stepp, David W. ; Zhou, Jiliang ; Wang, Yusi ; Weintraub, Daniel S. ; Traber, Peter ; Snider, William ; Jonigk, Danny ; Sullivan, Jennifer ; Ryan Crislip, G. ; Butcher, Joshua T. ; Thompson, Jennifer ; Su, Yunchao ; Chen, Feng ; Fulton, David J.R. / Galectin-3 is expressed in vascular smooth muscle cells and promotes pulmonary hypertension through changes in proliferation, apoptosis, and fibrosis. In: American Journal of Physiology - Lung Cellular and Molecular Physiology. 2019 ; Vol. 316, No. 5. pp. L784-L797.
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abstract = "A defining characteristic of pulmonary hypertension (PH) is the extensive remodeling of pulmonary arteries (PAs), which results in progressive increases in vascular resistance and stiffness and eventual failure of the right ventricle. There is no cure for PH and identification of novel molecular mechanisms that underlie increased proliferation, reduced apoptosis, and excessive extracellular matrix production in pulmonary artery smooth muscle cells (PASMCs) is a vital objective. Galectin-3 (Gal-3) is a chimeric lectin and potent driver of many aspects of fibrosis, but its role in regulating PASMC behavior in PH remains poorly understood. Herein, we evaluated the importance of increased Gal-3 expression and signaling on PA vascular remodeling and cardiopulmonary function in experimental models of PH. Gal-3 expression was quantified by qRT-PCR, immunoblotting, and immunofluorescence imaging, and its functional role was assessed by specific Gal-3 inhibitors and CRISPR/Cas9-mediated knockout of Gal-3 in the rat. In rat models of PH, we observed increased Gal-3 expression in PASMCs, which stimulated migration and resistance to apoptosis, whereas silencing or genetic deletion reduced cellular migration and PA fibrosis and increased apoptosis. Gal-3 inhibitors attenuated and reversed PA remodeling and fibrosis, as well as hemodynamic indices in monocrotaline (MCT)-treated rats in vivo. These results were supported by genetic deletion of Gal-3 in both MCT and Sugen Hypoxia rat models. In conclusion, our results suggest that elevated Gal-3 levels contribute to inappropriate PA remodeling in PH by enhancing multiple profibrotic mechanisms. Therapeutic strategies targeting Gal-3 may be of benefit in the treatment of PH.",
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T1 - Galectin-3 is expressed in vascular smooth muscle cells and promotes pulmonary hypertension through changes in proliferation, apoptosis, and fibrosis

AU - Barman, Scott A.

AU - Li, Xueyi

AU - Haigh, Stephen

AU - Kondrikov, Dmitry

AU - Mahboubi, Keyvan

AU - Bordan, Zsuzsanna

AU - Stepp, David W.

AU - Zhou, Jiliang

AU - Wang, Yusi

AU - Weintraub, Daniel S.

AU - Traber, Peter

AU - Snider, William

AU - Jonigk, Danny

AU - Sullivan, Jennifer

AU - Ryan Crislip, G.

AU - Butcher, Joshua T.

AU - Thompson, Jennifer

AU - Su, Yunchao

AU - Chen, Feng

AU - Fulton, David J.R.

PY - 2019/5

Y1 - 2019/5

N2 - A defining characteristic of pulmonary hypertension (PH) is the extensive remodeling of pulmonary arteries (PAs), which results in progressive increases in vascular resistance and stiffness and eventual failure of the right ventricle. There is no cure for PH and identification of novel molecular mechanisms that underlie increased proliferation, reduced apoptosis, and excessive extracellular matrix production in pulmonary artery smooth muscle cells (PASMCs) is a vital objective. Galectin-3 (Gal-3) is a chimeric lectin and potent driver of many aspects of fibrosis, but its role in regulating PASMC behavior in PH remains poorly understood. Herein, we evaluated the importance of increased Gal-3 expression and signaling on PA vascular remodeling and cardiopulmonary function in experimental models of PH. Gal-3 expression was quantified by qRT-PCR, immunoblotting, and immunofluorescence imaging, and its functional role was assessed by specific Gal-3 inhibitors and CRISPR/Cas9-mediated knockout of Gal-3 in the rat. In rat models of PH, we observed increased Gal-3 expression in PASMCs, which stimulated migration and resistance to apoptosis, whereas silencing or genetic deletion reduced cellular migration and PA fibrosis and increased apoptosis. Gal-3 inhibitors attenuated and reversed PA remodeling and fibrosis, as well as hemodynamic indices in monocrotaline (MCT)-treated rats in vivo. These results were supported by genetic deletion of Gal-3 in both MCT and Sugen Hypoxia rat models. In conclusion, our results suggest that elevated Gal-3 levels contribute to inappropriate PA remodeling in PH by enhancing multiple profibrotic mechanisms. Therapeutic strategies targeting Gal-3 may be of benefit in the treatment of PH.

AB - A defining characteristic of pulmonary hypertension (PH) is the extensive remodeling of pulmonary arteries (PAs), which results in progressive increases in vascular resistance and stiffness and eventual failure of the right ventricle. There is no cure for PH and identification of novel molecular mechanisms that underlie increased proliferation, reduced apoptosis, and excessive extracellular matrix production in pulmonary artery smooth muscle cells (PASMCs) is a vital objective. Galectin-3 (Gal-3) is a chimeric lectin and potent driver of many aspects of fibrosis, but its role in regulating PASMC behavior in PH remains poorly understood. Herein, we evaluated the importance of increased Gal-3 expression and signaling on PA vascular remodeling and cardiopulmonary function in experimental models of PH. Gal-3 expression was quantified by qRT-PCR, immunoblotting, and immunofluorescence imaging, and its functional role was assessed by specific Gal-3 inhibitors and CRISPR/Cas9-mediated knockout of Gal-3 in the rat. In rat models of PH, we observed increased Gal-3 expression in PASMCs, which stimulated migration and resistance to apoptosis, whereas silencing or genetic deletion reduced cellular migration and PA fibrosis and increased apoptosis. Gal-3 inhibitors attenuated and reversed PA remodeling and fibrosis, as well as hemodynamic indices in monocrotaline (MCT)-treated rats in vivo. These results were supported by genetic deletion of Gal-3 in both MCT and Sugen Hypoxia rat models. In conclusion, our results suggest that elevated Gal-3 levels contribute to inappropriate PA remodeling in PH by enhancing multiple profibrotic mechanisms. Therapeutic strategies targeting Gal-3 may be of benefit in the treatment of PH.

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KW - Fibrosis

KW - Galectin-3

KW - Knockout rat

KW - Pulmonary hypertension

KW - Vascular smooth muscle

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