Rho-kinase pathway activation and apoptosis in circulating leucocytes in patients with heart failure with reduced ejection fraction

Maria Paz Ocaranza; Jackeline Moya; Jorge E. Jalil; Sergio Lavandero; Alexis M. Kalergis; Cristián Molina; Luigi Gabrielli; Iván Godoy; Samuel Córdova; Pablo Castro; Paul Mac Nab; Victor Rossel; Lorena García; Javier González; Cristián Mancilla; Camila Fierro; Luis Farías

doi:10.1111/jcmm.14819

Rho-kinase pathway activation and apoptosis in circulating leucocytes in patients with heart failure with reduced ejection fraction

Maria Paz Ocaranza, Jackeline Moya, Jorge E. Jalil, Sergio Lavandero, Alexis M. Kalergis, Cristián Molina, Luigi Gabrielli, Iván Godoy, Samuel Córdova, Pablo Castro, Paul Mac Nab, Victor Rossel, Lorena García, Javier González, Cristián Mancilla, Camila Fierro, Luis Farías

Universidad de Chile

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

8 Citations (Scopus)

Abstract

Background: Increased Rho-kinase activity in circulating leucocytes is observed in heart failure with reduced ejection fraction (HFrEF). However, there is little information in HFrEF regarding other Rho-kinase pathway components an on the relationship between Rho-kinase and apoptosis. Here, Rho-kinase activation levels and phosphorylation of major downstream molecules and apoptosis levels were measured for the first time both in HFrEF patients and healthy individuals. Methods: Cross-sectional study comparing HFrEF patients (n = 20) and healthy controls (n = 19). Rho-kinase activity in circulating leucocytes (peripheral blood mononuclear cells, PBMCs) was determined by myosin light chain phosphatase 1 (MYPT1) and ezrin-radixin-moesin (ERM) phosphorylation. Rho-kinase cascade proteins phosphorylation p38-MAPK, myosin light chain-2, JAK and JNK were also analysed along with apoptosis. Results: MYPT1 and ERM phosphorylation were significantly elevated in HFrEF patients, (3.9- and 4.8-fold higher than in controls, respectively). JAK phosphorylation was significantly increased by 300% over controls. Phosphorylation of downstream molecules p38-MAPK and myosin light chain-2 was significantly higher by 360% and 490%, respectively, while JNK phosphorylation was reduced by 60%. Catecholamine and angiotensin II levels were significantly higher in HFrEF patients, while angiotensin-(1-9) levels were lower. Apoptosis in circulating leucocytes was significantly increased in HFrEF patients by 2.8-fold compared with controls and significantly correlated with Rho-kinase activation. Conclusion: Rho-kinase pathway is activated in PMBCs from HFrEF patients despite optimal treatment, and it is closely associated with neurohormonal activation and with apoptosis. ROCK cascade inhibition might induce clinical benefits in HFrEF patients, and its assessment in PMBCs could be useful to evaluate reverse remodelling and disease regression.

Original language	English
Pages (from-to)	1413-1427
Number of pages	15
Journal	Journal of Cellular and Molecular Medicine
Volume	24
Issue number	2
DOIs	https://doi.org/10.1111/jcmm.14819
Publication status	Published - Jan 1 2020

Bibliographical note

Publisher Copyright:
© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Funding

We acknowledge Ivonne Padilla for her work with the clinical samples and Roberto Gómez for his work with flow cytometry. This work was supported by grants from Fondecyt Chile (grants 1161739 1121060 and 1150862), from Millennium Institute Chile on Immunology and Immunotherapy (grant P09/016‐F) and from FONDAP Chile (grant 15130011). ,

Funders	Funder number
Fogarty International Center	R21TW011508
Fondo Nacional de Desarrollo Científico y Tecnológico	P09/016‐F, 1150862, 1161739 1121060
Fondo de Financiamiento de Centros de Investigación en Áreas Prioritarias	15130011

ASJC Scopus Subject Areas

Molecular Medicine
Cell Biology

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10.1111/jcmm.14819

Cite this

Ocaranza, M. P., Moya, J., Jalil, J. E., Lavandero, S., Kalergis, A. M., Molina, C., Gabrielli, L., Godoy, I., Córdova, S., Castro, P., Mac Nab, P., Rossel, V., García, L., González, J., Mancilla, C., Fierro, C., & Farías, L. (2020). Rho-kinase pathway activation and apoptosis in circulating leucocytes in patients with heart failure with reduced ejection fraction. Journal of Cellular and Molecular Medicine, 24(2), 1413-1427. https://doi.org/10.1111/jcmm.14819

Ocaranza, MP, Moya, J, Jalil, JE, Lavandero, S, Kalergis, AM, Molina, C, Gabrielli, L, Godoy, I, Córdova, S, Castro, P, Mac Nab, P, Rossel, V, García, L, González, J, Mancilla, C, Fierro, C & Farías, L 2020, 'Rho-kinase pathway activation and apoptosis in circulating leucocytes in patients with heart failure with reduced ejection fraction', Journal of Cellular and Molecular Medicine, vol. 24, no. 2, pp. 1413-1427. https://doi.org/10.1111/jcmm.14819

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title = "Rho-kinase pathway activation and apoptosis in circulating leucocytes in patients with heart failure with reduced ejection fraction",

abstract = "Background: Increased Rho-kinase activity in circulating leucocytes is observed in heart failure with reduced ejection fraction (HFrEF). However, there is little information in HFrEF regarding other Rho-kinase pathway components an on the relationship between Rho-kinase and apoptosis. Here, Rho-kinase activation levels and phosphorylation of major downstream molecules and apoptosis levels were measured for the first time both in HFrEF patients and healthy individuals. Methods: Cross-sectional study comparing HFrEF patients (n = 20) and healthy controls (n = 19). Rho-kinase activity in circulating leucocytes (peripheral blood mononuclear cells, PBMCs) was determined by myosin light chain phosphatase 1 (MYPT1) and ezrin-radixin-moesin (ERM) phosphorylation. Rho-kinase cascade proteins phosphorylation p38-MAPK, myosin light chain-2, JAK and JNK were also analysed along with apoptosis. Results: MYPT1 and ERM phosphorylation were significantly elevated in HFrEF patients, (3.9- and 4.8-fold higher than in controls, respectively). JAK phosphorylation was significantly increased by 300% over controls. Phosphorylation of downstream molecules p38-MAPK and myosin light chain-2 was significantly higher by 360% and 490%, respectively, while JNK phosphorylation was reduced by 60%. Catecholamine and angiotensin II levels were significantly higher in HFrEF patients, while angiotensin-(1-9) levels were lower. Apoptosis in circulating leucocytes was significantly increased in HFrEF patients by 2.8-fold compared with controls and significantly correlated with Rho-kinase activation. Conclusion: Rho-kinase pathway is activated in PMBCs from HFrEF patients despite optimal treatment, and it is closely associated with neurohormonal activation and with apoptosis. ROCK cascade inhibition might induce clinical benefits in HFrEF patients, and its assessment in PMBCs could be useful to evaluate reverse remodelling and disease regression.",

author = "Ocaranza, {Maria Paz} and Jackeline Moya and Jalil, {Jorge E.} and Sergio Lavandero and Kalergis, {Alexis M.} and Cristi{\'a}n Molina and Luigi Gabrielli and Iv{\'a}n Godoy and Samuel C{\'o}rdova and Pablo Castro and {Mac Nab}, Paul and Victor Rossel and Lorena Garc{\'i}a and Javier Gonz{\'a}lez and Cristi{\'a}n Mancilla and Camila Fierro and Luis Far{\'i}as",

note = "Publisher Copyright: {\textcopyright} 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.",

year = "2020",

month = jan,

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doi = "10.1111/jcmm.14819",

language = "English",

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T1 - Rho-kinase pathway activation and apoptosis in circulating leucocytes in patients with heart failure with reduced ejection fraction

AU - Ocaranza, Maria Paz

AU - Moya, Jackeline

AU - Jalil, Jorge E.

AU - Lavandero, Sergio

AU - Kalergis, Alexis M.

AU - Molina, Cristián

AU - Gabrielli, Luigi

AU - Godoy, Iván

AU - Córdova, Samuel

AU - Castro, Pablo

AU - Mac Nab, Paul

AU - Rossel, Victor

AU - García, Lorena

AU - González, Javier

AU - Mancilla, Cristián

AU - Fierro, Camila

AU - Farías, Luis

PY - 2020/1/1

Y1 - 2020/1/1

N2 - Background: Increased Rho-kinase activity in circulating leucocytes is observed in heart failure with reduced ejection fraction (HFrEF). However, there is little information in HFrEF regarding other Rho-kinase pathway components an on the relationship between Rho-kinase and apoptosis. Here, Rho-kinase activation levels and phosphorylation of major downstream molecules and apoptosis levels were measured for the first time both in HFrEF patients and healthy individuals. Methods: Cross-sectional study comparing HFrEF patients (n = 20) and healthy controls (n = 19). Rho-kinase activity in circulating leucocytes (peripheral blood mononuclear cells, PBMCs) was determined by myosin light chain phosphatase 1 (MYPT1) and ezrin-radixin-moesin (ERM) phosphorylation. Rho-kinase cascade proteins phosphorylation p38-MAPK, myosin light chain-2, JAK and JNK were also analysed along with apoptosis. Results: MYPT1 and ERM phosphorylation were significantly elevated in HFrEF patients, (3.9- and 4.8-fold higher than in controls, respectively). JAK phosphorylation was significantly increased by 300% over controls. Phosphorylation of downstream molecules p38-MAPK and myosin light chain-2 was significantly higher by 360% and 490%, respectively, while JNK phosphorylation was reduced by 60%. Catecholamine and angiotensin II levels were significantly higher in HFrEF patients, while angiotensin-(1-9) levels were lower. Apoptosis in circulating leucocytes was significantly increased in HFrEF patients by 2.8-fold compared with controls and significantly correlated with Rho-kinase activation. Conclusion: Rho-kinase pathway is activated in PMBCs from HFrEF patients despite optimal treatment, and it is closely associated with neurohormonal activation and with apoptosis. ROCK cascade inhibition might induce clinical benefits in HFrEF patients, and its assessment in PMBCs could be useful to evaluate reverse remodelling and disease regression.

AB - Background: Increased Rho-kinase activity in circulating leucocytes is observed in heart failure with reduced ejection fraction (HFrEF). However, there is little information in HFrEF regarding other Rho-kinase pathway components an on the relationship between Rho-kinase and apoptosis. Here, Rho-kinase activation levels and phosphorylation of major downstream molecules and apoptosis levels were measured for the first time both in HFrEF patients and healthy individuals. Methods: Cross-sectional study comparing HFrEF patients (n = 20) and healthy controls (n = 19). Rho-kinase activity in circulating leucocytes (peripheral blood mononuclear cells, PBMCs) was determined by myosin light chain phosphatase 1 (MYPT1) and ezrin-radixin-moesin (ERM) phosphorylation. Rho-kinase cascade proteins phosphorylation p38-MAPK, myosin light chain-2, JAK and JNK were also analysed along with apoptosis. Results: MYPT1 and ERM phosphorylation were significantly elevated in HFrEF patients, (3.9- and 4.8-fold higher than in controls, respectively). JAK phosphorylation was significantly increased by 300% over controls. Phosphorylation of downstream molecules p38-MAPK and myosin light chain-2 was significantly higher by 360% and 490%, respectively, while JNK phosphorylation was reduced by 60%. Catecholamine and angiotensin II levels were significantly higher in HFrEF patients, while angiotensin-(1-9) levels were lower. Apoptosis in circulating leucocytes was significantly increased in HFrEF patients by 2.8-fold compared with controls and significantly correlated with Rho-kinase activation. Conclusion: Rho-kinase pathway is activated in PMBCs from HFrEF patients despite optimal treatment, and it is closely associated with neurohormonal activation and with apoptosis. ROCK cascade inhibition might induce clinical benefits in HFrEF patients, and its assessment in PMBCs could be useful to evaluate reverse remodelling and disease regression.

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Rho-kinase pathway activation and apoptosis in circulating leucocytes in patients with heart failure with reduced ejection fraction

Abstract

Bibliographical note

Funding

ASJC Scopus Subject Areas

Access to Document

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