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TGF-β1 induced up-regulation of B1 kinin receptor promotes antifibrotic activity in rat cardiac myofibroblasts.

Abstract

Cardiac myofibroblast (CMF) are non-muscle cardiac cells that play a crucial role in wound healing and in pathological remodeling. These cells are mainly derived of cardiac fibroblast (CF) differentiation mediated by TGF-β1. Evidence suggests that bradykinin (BK) regulates cardiac fibroblast function in the heart. Both B1 and B2 kinin receptors (B1R and B2R, respectively) mediate the biological effects of kinins. We recently showed that both receptors are expressed in CMF and its stimulation decreases collagen secretion. Whether TGF-β1 regulates B1R and B2R expression, and how these receptors control antifibrotic activity in CMF remains poorly understood. In this work, we sought to study, the regulation of B1R expression in cultured CMF mediated by TGF-β1, and the molecular mechanisms involved in B1R activation on CMF intracellular collagen type-I levels. Cardiac fibroblast-primary culture was obtained from neonatal rats. Hearts were digested and CFs were attached to dishes and separated from cardiomyoctes. CMF were obtained from CF differentiation with TGF-β1 5 ng/mL. CF and CMF were treated with B1R and B2R agonists and with TGF-β1 at different times and concentrations, in the presence or absence of chemical inhibitors, to evaluate signaling pathways involved in B1R expression, collagen type-I and prostacyclin levels. B1R and collagen type-I levels were evaluated by western blot. Prostacyclin levels were quantified by an ELISA kit. TGF-β1 increased B1R expression via TGFβ type I receptor kinase (ALK5) activation and its subsequent signaling pathways involving Smad2, p38, JNK and ERK1/2 activation. Moreover, in CMF, the activation of B1R and B2R by their respective agonists, reduced collagen synthesis. This effect was mediated by the canonical signaling pathway; phospholipase C (PLC), protein kinase C (PKC), phospholipase A2 (PLA2), COX-2 activation and PGI2 secretion and its autocrine effect. TGF-β1 through ALK5, Smad2, p38, JNK and ERK1/2 increases B1R expression; whereas in CMF, B1R and B2R activation share common signaling pathways for reducing collagen synthesis.

Authors+Show Affiliations

Programa de Farmacología Molecular y Clínica, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.Escuela de Química y Farmacia, Facultad de Medicina, Universidad Andres Bello, 2520000, Viña del Mar, Chile.Laboratorio de Farmacología Molecular, Departamento de Química Farmacológica y Toxicológica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile.Laboratorio de Farmacología Molecular, Departamento de Química Farmacológica y Toxicológica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile.Laboratorio de Farmacología Molecular, Departamento de Química Farmacológica y Toxicológica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile.Programa de Farmacología Molecular y Clínica, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.Programa de Farmacología Molecular y Clínica, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.Laboratorio de Farmacología Molecular, Departamento de Química Farmacológica y Toxicológica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile.Laboratorio de Farmacología Molecular, Departamento de Química Farmacológica y Toxicológica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile.Laboratorio de Bioquímica Molecular, Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile. Advanced Center of Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Olivos 1007, 8380492, Santiago, Chile.Laboratorio de Farmacología Molecular, Departamento de Química Farmacológica y Toxicológica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile. gadiaz@ciq.uchile.cl. Advanced Center of Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Olivos 1007, 8380492, Santiago, Chile. gadiaz@ciq.uchile.cl.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31309451

Citation

Catalán, Mabel, et al. "TGF-β1 Induced Up-regulation of B1 Kinin Receptor Promotes Antifibrotic Activity in Rat Cardiac Myofibroblasts." Molecular Biology Reports, 2019.
Catalán M, Aránguiz P, Boza P, et al. TGF-β1 induced up-regulation of B1 kinin receptor promotes antifibrotic activity in rat cardiac myofibroblasts. Mol Biol Rep. 2019.
Catalán, M., Aránguiz, P., Boza, P., Olmedo, I., Humeres, C., Vivar, R., ... Díaz-Araya, G. (2019). TGF-β1 induced up-regulation of B1 kinin receptor promotes antifibrotic activity in rat cardiac myofibroblasts. Molecular Biology Reports, doi:10.1007/s11033-019-04977-3.
Catalán M, et al. TGF-β1 Induced Up-regulation of B1 Kinin Receptor Promotes Antifibrotic Activity in Rat Cardiac Myofibroblasts. Mol Biol Rep. 2019 Jul 15; PubMed PMID: 31309451.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - TGF-β1 induced up-regulation of B1 kinin receptor promotes antifibrotic activity in rat cardiac myofibroblasts. AU - Catalán,Mabel, AU - Aránguiz,Pablo, AU - Boza,Pía, AU - Olmedo,Ivonne, AU - Humeres,Claudio, AU - Vivar,Raúl, AU - Anfossi,Renatto, AU - Ayala,Pedro, AU - Espinoza,Claudio, AU - Lavandero,Sergio, AU - Díaz-Araya,Guillermo, Y1 - 2019/07/15/ PY - 2019/02/14/received PY - 2019/07/11/accepted PY - 2019/7/17/entrez KW - Cardiac KW - Collagen KW - Kinin receptors KW - Myofibroblasts JF - Molecular biology reports JO - Mol. Biol. Rep. N2 - Cardiac myofibroblast (CMF) are non-muscle cardiac cells that play a crucial role in wound healing and in pathological remodeling. These cells are mainly derived of cardiac fibroblast (CF) differentiation mediated by TGF-β1. Evidence suggests that bradykinin (BK) regulates cardiac fibroblast function in the heart. Both B1 and B2 kinin receptors (B1R and B2R, respectively) mediate the biological effects of kinins. We recently showed that both receptors are expressed in CMF and its stimulation decreases collagen secretion. Whether TGF-β1 regulates B1R and B2R expression, and how these receptors control antifibrotic activity in CMF remains poorly understood. In this work, we sought to study, the regulation of B1R expression in cultured CMF mediated by TGF-β1, and the molecular mechanisms involved in B1R activation on CMF intracellular collagen type-I levels. Cardiac fibroblast-primary culture was obtained from neonatal rats. Hearts were digested and CFs were attached to dishes and separated from cardiomyoctes. CMF were obtained from CF differentiation with TGF-β1 5 ng/mL. CF and CMF were treated with B1R and B2R agonists and with TGF-β1 at different times and concentrations, in the presence or absence of chemical inhibitors, to evaluate signaling pathways involved in B1R expression, collagen type-I and prostacyclin levels. B1R and collagen type-I levels were evaluated by western blot. Prostacyclin levels were quantified by an ELISA kit. TGF-β1 increased B1R expression via TGFβ type I receptor kinase (ALK5) activation and its subsequent signaling pathways involving Smad2, p38, JNK and ERK1/2 activation. Moreover, in CMF, the activation of B1R and B2R by their respective agonists, reduced collagen synthesis. This effect was mediated by the canonical signaling pathway; phospholipase C (PLC), protein kinase C (PKC), phospholipase A2 (PLA2), COX-2 activation and PGI2 secretion and its autocrine effect. TGF-β1 through ALK5, Smad2, p38, JNK and ERK1/2 increases B1R expression; whereas in CMF, B1R and B2R activation share common signaling pathways for reducing collagen synthesis. SN - 1573-4978 UR - https://www.unboundmedicine.com/medline/citation/31309451/TGF-β1_induced_up-regulation_of_B1_kinin_receptor_promotes_antifibrotic_activity_in_rat_cardiac_myofibroblasts L2 - https://doi.org/10.1007/s11033-019-04977-3 DB - PRIME DP - Unbound Medicine ER -