Camila Fierro1, Ulises Novoa2, Veronica González1, María Paz Ocaranza3, Jorge E Jalil4. 1. Division of Cardiovascular Diseases, School of Medicine, Pontificia Universidad Católica de Chile, Chile. 2. Department of Biomedical Sciences, Facultad de Ciencias de la Salud, Universidad de Talca, Chile. 3. Division of Cardiovascular Diseases, School of Medicine, Pontificia Universidad Católica de Chile, Chile; Advanced Center for Chronic Diseases (ACCDis), Faculty of Medicine, Pontificia Universidad Católica de Chile, Chile. 4. Division of Cardiovascular Diseases, School of Medicine, Pontificia Universidad Católica de Chile, Chile. Electronic address: jjalil@med.puc.cl.
Abstract
BACKGROUND: The small guanosine triphosphatase RhoA and its direct target Rho kinase (ROCK) play important roles in cardiovascular pathophysiology. Activated ROCK phosphorylates intracellular proteins with detrimental effects on cardiovascular remodeling. Increased ROCK activity in circulating leukocytes is observed in hypertension and in heart failure, but its relationship with ROCK activation in the myocardium and vessels is unknown. We hypothesized that ROCK activation and phosphorylation/activation of some of its key downstream molecules in the heart and arterial wall are reflected in circulating leukocytes. METHODS: Phosphorylation of MYPT1, ERM and p38-MAPK and levels of p65-NF-κB were determined in the left ventricle (LV), aortic wall and circulating leukocytes in rats with high (Brown Norway, BN) and low (Lewis) angiotensin converting enzyme. A group of BN rats received the ROCK inhibitor fasudil (7days). RESULTS: Compared to Lewis rats, in the BN group phosphorylated levels of MYPT1, ERM and p38-MAPK and levels of p65-NF-κB were increased (P<0.05) in the LV (67%, 92%, 52% and 98%, respectively); in the aortic wall (57%, 51%, 68% and 66%, respectively) and in circulating leukocytes (61%, 72%, 49% and 105%, respectively). Fasudil reduced all these levels to those observed in Lewis rats. Phosphorylated MYPT1, ERM, and p38-MAPK and levels of p65-NF-κB in circulating leukocytes were significantly correlated with their respective LV and aortic wall levels (excepting p65-NF-κB in aorta). CONCLUSION: ROCK activity in circulating leukocytes reflects activation of this signaling pathway in the myocardium and aortic wall in this model, and supports its value as a potential cardiovascular remodeling marker.
BACKGROUND: The small guanosine triphosphatase RhoA and its direct target Rho kinase (ROCK) play important roles in cardiovascular pathophysiology. Activated ROCK phosphorylates intracellular proteins with detrimental effects on cardiovascular remodeling. Increased ROCK activity in circulating leukocytes is observed in hypertension and in heart failure, but its relationship with ROCK activation in the myocardium and vessels is unknown. We hypothesized that ROCK activation and phosphorylation/activation of some of its key downstream molecules in the heart and arterial wall are reflected in circulating leukocytes. METHODS: Phosphorylation of MYPT1, ERM and p38-MAPK and levels of p65-NF-κB were determined in the left ventricle (LV), aortic wall and circulating leukocytes in rats with high (Brown Norway, BN) and low (Lewis) angiotensin converting enzyme. A group of BNrats received the ROCK inhibitor fasudil (7days). RESULTS: Compared to Lewis rats, in the BN group phosphorylated levels of MYPT1, ERM and p38-MAPK and levels of p65-NF-κB were increased (P<0.05) in the LV (67%, 92%, 52% and 98%, respectively); in the aortic wall (57%, 51%, 68% and 66%, respectively) and in circulating leukocytes (61%, 72%, 49% and 105%, respectively). Fasudil reduced all these levels to those observed in Lewis rats. Phosphorylated MYPT1, ERM, and p38-MAPK and levels of p65-NF-κB in circulating leukocytes were significantly correlated with their respective LV and aortic wall levels (excepting p65-NF-κB in aorta). CONCLUSION: ROCK activity in circulating leukocytes reflects activation of this signaling pathway in the myocardium and aortic wall in this model, and supports its value as a potential cardiovascular remodeling marker.
Authors: Maria Paz Ocaranza; Jorge E Jalil; Rodrigo Altamirano; Ana de León; Jackeline Moya; Alejandra Lonis; Luigi Gabrielli; Paul Mac Nab; Samuel Córdova; Alejandro Paredes; Ismael Vergara; Alex Bittner; Karime Sabat; Karla Pastorini Journal: Front Pharmacol Date: 2021-04-23 Impact factor: 5.810
Authors: 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 Journal: J Cell Mol Med Date: 2019-11-28 Impact factor: 5.310
Authors: Tadeu L Montagnoli; Jaqueline S da Silva; Susumu Z Sudo; Aimeé D Santos; Gabriel F Gomide; Mauro P L de Sá; Gisele Zapata-Sudo Journal: Cells Date: 2021-06-30 Impact factor: 7.666