TY - JOUR
T1 - Arginase inhibition restores NOS coupling and reverses endothelial dysfunction and vascular stiffness in old rats
AU - Jae, Hyung Kim
AU - Bugaj, Lukasz J.
AU - Young, Jun Oh
AU - Bivalacqua, Trinity J.
AU - Ryoo, Sungwoo
AU - Soucy, Kevin G.
AU - Santhanam, Lakshmi
AU - Webb, Alanah
AU - Camara, Andre
AU - Sikka, Gautam
AU - Nyhan, Daniel
AU - Shoukas, Artin A.
AU - Ilies, Monica
AU - Christianson, David W.
AU - Champion, Hunter C.
AU - Berkowitz, Dan E.
PY - 2009/10
Y1 - 2009/10
N2 - There is increasing evidence that upregulation of arginase contributes to impaired endothelial function in aging. In this study, we demonstrate that arginase upregulation leads to endothelial nitric oxide synthase (eNOS) uncoupling and that in vivo chronic inhibition of arginase restores nitroso-redox balance, improves endothelial function, and increases vascular compliance in old rats. Arginase activity in old rats was significantly increased compared with that shown in young rats. Old rats had significantly lower nitric oxide (NO) and higher superoxide (O2-) production than young. Acute inhibition of both NOS, with NG-nitro-L- arginine methyl ester, and arginase, with 2(S)-amino-6-boronohexanoic acid (ABH), significantly reduced O2- production in old rats but not in young. In addition, the ratio of eNOS dimer to monomer in old rats was significantly decreased compared with that shown in young rats. These results suggest that eNOS was uncoupled in old rats. Although the expression of arginase 1 and eNOS was similar in young and old rats, inducible NOS (iNOS) was significantly upregulated. Furthermore, S-nitrosylation of arginase 1 was significantly elevated in old rats. These findings support our previously published finding that iNOS nitrosylates and activates arginase 1 (Santhanam et al., Circ Res 101: 692-702, 2007). Chronic arginase inhibition in old rats preserved eNOS dimer-to-monomer ratio and significantly reduced O 2- production and enhanced endothelial-dependent vasorelaxation to ACh. In addition, ABH significantly reduced vascular stiffness in old rats. These data indicate that iNOS-dependent S-nitrosylation of arginase 1 and the increase in arginase activity lead to eNOS uncoupling, contributing to the nitroso-redox imbalance, endothelial dysfunction, and vascular stiffness observed in vascular aging. We suggest that arginase is a viable target for therapy in age-dependent vascular stiffness.
AB - There is increasing evidence that upregulation of arginase contributes to impaired endothelial function in aging. In this study, we demonstrate that arginase upregulation leads to endothelial nitric oxide synthase (eNOS) uncoupling and that in vivo chronic inhibition of arginase restores nitroso-redox balance, improves endothelial function, and increases vascular compliance in old rats. Arginase activity in old rats was significantly increased compared with that shown in young rats. Old rats had significantly lower nitric oxide (NO) and higher superoxide (O2-) production than young. Acute inhibition of both NOS, with NG-nitro-L- arginine methyl ester, and arginase, with 2(S)-amino-6-boronohexanoic acid (ABH), significantly reduced O2- production in old rats but not in young. In addition, the ratio of eNOS dimer to monomer in old rats was significantly decreased compared with that shown in young rats. These results suggest that eNOS was uncoupled in old rats. Although the expression of arginase 1 and eNOS was similar in young and old rats, inducible NOS (iNOS) was significantly upregulated. Furthermore, S-nitrosylation of arginase 1 was significantly elevated in old rats. These findings support our previously published finding that iNOS nitrosylates and activates arginase 1 (Santhanam et al., Circ Res 101: 692-702, 2007). Chronic arginase inhibition in old rats preserved eNOS dimer-to-monomer ratio and significantly reduced O 2- production and enhanced endothelial-dependent vasorelaxation to ACh. In addition, ABH significantly reduced vascular stiffness in old rats. These data indicate that iNOS-dependent S-nitrosylation of arginase 1 and the increase in arginase activity lead to eNOS uncoupling, contributing to the nitroso-redox imbalance, endothelial dysfunction, and vascular stiffness observed in vascular aging. We suggest that arginase is a viable target for therapy in age-dependent vascular stiffness.
KW - Aging
KW - NOS uncoupling
KW - Nitric oxide
KW - S-nitrosylation
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U2 - 10.1152/japplphysiol.91393.2008
DO - 10.1152/japplphysiol.91393.2008
M3 - Article
C2 - 19661445
AN - SCOPUS:70350117109
SN - 8750-7587
VL - 107
SP - 1249
EP - 1257
JO - Journal of applied physiology
JF - Journal of applied physiology
IS - 4
ER -