mPGES-1 (Microsomal Prostaglandin E Synthase-1) Mediates Vascular Dysfunction in Hypertension Through Oxidative Stress
Por:
Avendano, MS, Garcia-Redondo, AB, Zalba, G, Gonzalez-Amor, M, Aguado, A, Martinez-Revelles, S, Beltran, LM, Camacho, M, Cachofeiro, V, Alonso, MJ, Salaices, M, Briones, AM
Publicada:
1 ago 2018
Resumen:
mPGES-1 (microsomal prostaglandin E synthase-1), the downstream enzyme responsible for PGE(2) (prostaglandin E-2) synthesis in inflammatory conditions and oxidative stress are increased in vessels from hypertensive animals. We evaluated the role of mPGES-1-derived PGE(2) in the vascular dysfunction and remodeling in hypertension and the possible contribution of oxidative stress. We used human peripheral blood mononuclear cells from asymptomatic patients, arteries from untreated and Ang II (angiotensin II)-infused mPGES-1(-/-) and mPGES-1(+/+) mice, and vascular smooth muscle cells exposed to PGE(2). In human cells, we found a positive correlation between mPGES-1 mRNA and carotid intima-media thickness (r=0.637; P<0.001) and with NADPH oxidase-dependent superoxide production (r=0.417; P<0.001). In Ang II-infused mice, mPGES-1 deletion prevented all of the following: (1) the augmented wall:lumen ratio, vascular stiffness, and altered elastin structure; (2) the increased gene expression of profibrotic and proinflammatory markers; (3) the increased vasoconstrictor responses and endothelial dysfunction; (4) the increased NADPH oxidase activity and the diminished mitochondrial membrane potential; and (5) the increased reactive oxygen species generation and reduced NO bioavailability. In vascular smooth muscle cells or aortic segments, PGE(2) increased NADPH oxidase expression and activity and reduced mitochondrial membrane potential, effects that were abolished by antagonists of the PGE(2) receptors (EP), EP1 and EP3, and by JNK (c-Jun N-terminal kinase) and ERK1/2 (extracellular-signal-regulated kinases 1/2) inhibition. Deletion of mPGES-1 augmented vascular production of PGI(2) suggesting rediversion of the accumulated PGH(2) substrate. In conclusion, mPGES-1-derived PGE(2) is involved in vascular remodeling, stiffness, and endothelial dysfunction in hypertension likely through an increase of oxidative stress produced by NADPH oxidase and mitochondria.
Filiaciones:
Avendano, MS:
Univ Autonoma Madrid, Inst Invest Hosp La Paz, Dept Farmacol, C Arzobispo Morcillo 4, Madrid 28029, Spain
Garcia-Redondo, AB:
Univ Autonoma Madrid, Inst Invest Hosp La Paz, Dept Farmacol, C Arzobispo Morcillo 4, Madrid 28029, Spain
Ctr Invest Biomed Red CIBER Enfermedades Cardiova, Madrid, Spain
Zalba, G:
Univ Navarra, Inst Invest Sanitaria Navarra, Dept Bioquim & Genet, Pamplona, Spain
Gonzalez-Amor, M:
Univ Autonoma Madrid, Inst Invest Hosp La Paz, Dept Farmacol, C Arzobispo Morcillo 4, Madrid 28029, Spain
Aguado, A:
Univ Autonoma Madrid, Inst Invest Hosp La Paz, Dept Farmacol, C Arzobispo Morcillo 4, Madrid 28029, Spain
Martinez-Revelles, S:
Univ Autonoma Madrid, Inst Invest Hosp La Paz, Dept Farmacol, C Arzobispo Morcillo 4, Madrid 28029, Spain
Ctr Invest Biomed Red CIBER Enfermedades Cardiova, Madrid, Spain
Beltran, LM:
Hosp Virgen Rocio, Inst Biomed Sevilla, Unidad Clin Expt Riesgo Vasc Med Interna, Seville, Spain
Camacho, M:
Ctr Invest Biomed Red CIBER Enfermedades Cardiova, Madrid, Spain
Inst Invest Biomed St Pau, Lab Angiol Biol Vasc & Inflamac, Barcelona, Spain
Cachofeiro, V:
Ctr Invest Biomed Red CIBER Enfermedades Cardiova, Madrid, Spain
Univ Complutense Madrid, Inst Invest Gregorio Maranon, Fac Med, Dept Fisiol, Madrid, Spain
Alonso, MJ:
Ctr Invest Biomed Red CIBER Enfermedades Cardiova, Madrid, Spain
Univ Rey Juan Carlos, Dept Ciencias Basicas Salud, Alcorcon, Spain
Salaices, M:
Univ Autonoma Madrid, Inst Invest Hosp La Paz, Dept Farmacol, C Arzobispo Morcillo 4, Madrid 28029, Spain
Ctr Invest Biomed Red CIBER Enfermedades Cardiova, Madrid, Spain
Briones, AM:
Univ Autonoma Madrid, Inst Invest Hosp La Paz, Dept Farmacol, C Arzobispo Morcillo 4, Madrid 28029, Spain
Ctr Invest Biomed Red CIBER Enfermedades Cardiova, Madrid, Spain
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