Arginase inhibition restores NOS coupling and reverses endothelial dysfunction and vascular stiffness in old rats.
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 N(G)-nitro-l-arginine methyl ester, and arginase, with 2S-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 O2(-) 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.
Kim
Jae Hyung
JH
Anesthesiology, Tower 711, Johns Hopkins Hospital, 600 N. Wolfe St., Baltimore, MD 21287, USA.
Bugaj
Lukasz J
LJ
Oh
Young Jun
YJ
Bivalacqua
Trinity J
TJ
Ryoo
Sungwoo
S
Soucy
Kevin G
KG
Santhanam
Lakshmi
L
Webb
Alanah
A
Camara
Andre
A
Sikka
Gautam
G
Nyhan
Daniel
D
Shoukas
Artin A
AA
Ilies
Monica
M
Christianson
David W
DW
Champion
Hunter C
HC
Berkowitz
Dan E
DE
D000109:Acetylcholine / Q000494:pharmacology; D000367:Age Factors; D000375:Aging; D000614:Aminocaproates / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D001119:Arginase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001896:Boron Compounds / Q000494:pharmacology*; D002339:Carotid Arteries / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D003187:Compliance; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010084:Oxidation-Reduction; D055503:Protein Multimerization; D051381:Rats; D011916:Rats, Inbred F344; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
C121228:2-amino-6-boronohexanoic acid; D000614:Aminocaproates; D001896:Boron Compounds; D004791:Enzyme Inhibitors; D014665:Vasodilator Agents; D013481:Superoxides; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; D001119:Arginase; C542908:arginase I, rat; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester