TY - JOUR
T1 - Arginase inhibition by (−)-Epicatechin reverses endothelial cell aging
AU - Garate-Carrillo, Alejandra
AU - Navarrete-Yañez, Viridiana
AU - Ortiz-Vilchis, Pilar
AU - Guevara, Gustavo
AU - Castillo, Carmen
AU - Mendoza-Lorenzo, Patricia
AU - Ceballos, Guillermo
AU - Ortiz-Flores, Miguel
AU - Najera, Nayelli
AU - Bustamante-Pozo, Moises Muratt
AU - Rubio-Gayosso, Ivan
AU - Villarreal, Francisco
AU - Ramirez-Sanchez, Israel
N1 - Publisher Copyright:
© 2020 Elsevier B.V.
PY - 2020/10/15
Y1 - 2020/10/15
N2 - Endothelial dysfunction (EnD) occurs with aging and endothelial nitric oxide (NO) production by NO synthase (NOS) can be impaired. Low NO levels have been linked to increased arginase (Ar) activity as Ar competes with NOS for L-arginine. The inhibition of Ar activity can reverse EnD and (−)-epicatechin (Epi) inhibits myocardial Ar activity. In this study, through in silico modeling we demonstrate that Epi interacts with Ar similarly to its inhibitor Norvaline (Norv). Using in vitro and in vivo models of aging, we examined Epi and Norv-inhibition of Ar activity and its endothelium-protective effects. Bovine coronary artery endothelial cells (BCAEC) were treated with Norv (10 μM), Epi (1 μM) or the combination (Epi + Norv) for 48 h. Ar activity increased in aged BCAEC, with decreased NO generation. Treatment decreased Ar activity to levels seen in young cells. Epi and Epi + Norv decreased nitrosylated Ar levels by ~25% in aged cells with lower oxidative stress (~25%) (dihydroethidium) levels. In aged cells, Epi and Epi + Norv restored the eNOS monomer/dimer ratio, protein expression levels and NO production to those of young cells. Furthermore, using 18 month old rats 15 days of treatment with either Epi (1 mg/kg), Norv (10 mg/kg) or combo, decreased hypertension and improved aorta vasorelaxation to acetylcholine, blood NO levels and tetra/dihydribiopterin ratios in cultured rat aortic endothelial cells. In conclusion, results provide evidence that inhibiting Ar with Epi reverses aged-related loss of eNOS function and improves vascular function through the modulation of Ar and eNOS protein levels and activity.
AB - Endothelial dysfunction (EnD) occurs with aging and endothelial nitric oxide (NO) production by NO synthase (NOS) can be impaired. Low NO levels have been linked to increased arginase (Ar) activity as Ar competes with NOS for L-arginine. The inhibition of Ar activity can reverse EnD and (−)-epicatechin (Epi) inhibits myocardial Ar activity. In this study, through in silico modeling we demonstrate that Epi interacts with Ar similarly to its inhibitor Norvaline (Norv). Using in vitro and in vivo models of aging, we examined Epi and Norv-inhibition of Ar activity and its endothelium-protective effects. Bovine coronary artery endothelial cells (BCAEC) were treated with Norv (10 μM), Epi (1 μM) or the combination (Epi + Norv) for 48 h. Ar activity increased in aged BCAEC, with decreased NO generation. Treatment decreased Ar activity to levels seen in young cells. Epi and Epi + Norv decreased nitrosylated Ar levels by ~25% in aged cells with lower oxidative stress (~25%) (dihydroethidium) levels. In aged cells, Epi and Epi + Norv restored the eNOS monomer/dimer ratio, protein expression levels and NO production to those of young cells. Furthermore, using 18 month old rats 15 days of treatment with either Epi (1 mg/kg), Norv (10 mg/kg) or combo, decreased hypertension and improved aorta vasorelaxation to acetylcholine, blood NO levels and tetra/dihydribiopterin ratios in cultured rat aortic endothelial cells. In conclusion, results provide evidence that inhibiting Ar with Epi reverses aged-related loss of eNOS function and improves vascular function through the modulation of Ar and eNOS protein levels and activity.
KW - Aging
KW - Arginase
KW - Endothelial dysfunction
KW - Epicatechin
KW - Nitric oxide synthase
KW - Norvaline
UR - http://www.scopus.com/inward/record.url?scp=85090191869&partnerID=8YFLogxK
U2 - 10.1016/j.ejphar.2020.173442
DO - 10.1016/j.ejphar.2020.173442
M3 - Artículo
C2 - 32795514
AN - SCOPUS:85090191869
SN - 0014-2999
VL - 885
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
M1 - 173442
ER -