Korean J Physiol Pharmacol.  2017 Jan;21(1):83-90. 10.4196/kjpp.2017.21.1.83.

Intravenous administration of piceatannol, an arginase inhibitor, improves endothelial dysfunction in aged mice

• Nguyen MC
• Ryoo S

• KMID: 2371071
• DOI: http://doi.org/10.4196/kjpp.2017.21.1.83

Abstract

Advanced age is one of the risk factors for vascular diseases that are mainly caused by impaired nitric oxide (NO) production. It has been demonstrated that endothelial arginase constrains the activity of endothelial nitric oxide synthase (eNOS) and limits NO generation. Hence, arginase inhibition is suggested to be vasoprotective in aging. In this study, we examined the effects of intravenous injection of Piceatannol, an arginase inhibitor, on aged mice. Our results show that Piceatannol administration reduced the blood pressure in aged mice by inhibiting arginase activity, which was associated with NO production and reactive oxygen species generation. In addition, Piceatannol administration recovered Ca²âº/calmodulin-dependent protein kinase II phosphorylation, eNOS phosphorylation and eNOS dimer stability in the aged mice. The improved NO signaling was shown to be effective in attenuating the phenylephrine-dependent contractile response and in enhancing the acetylcholine-dependent vasorelaxation response in aortic rings from the aged mice. These data suggest Piceatannol as a potential treatment for vascular disease.

Keyword

Age-associated diseases; Arginase inhibition; Endothelial dysfunction; Endothelial nitric oxide synthase; Intravenous injection; Piceatannol

MeSH Terms

Administration, Intravenous*
Aging
Animals
Arginase*
Blood Pressure
Injections, Intravenous
Mice*
Nitric Oxide
Nitric Oxide Synthase Type III
Phosphorylation
Protein Kinases
Reactive Oxygen Species
Risk Factors
Vascular Diseases
Vasodilation
Arginase
Nitric Oxide
Nitric Oxide Synthase Type III
Protein Kinases
Reactive Oxygen Species

Figure

• 

  Fig. 1 Piceatannol administration inhibits aortic arginase activity in aged mice.Arginase activity of isolated mouse aorta from each group (Young, Old, Old+Pc) was measured and represented as the percentage of that in the Young group (mean±SD). n=6 animals from each group. *p<0.01 vs. Young, †p<0.01 vs. Old.

• 

  Fig. 2 Arginase inhibition by Piceatannol restores NO and ROS balance in aged mice.(A) The NO level in the mouse aortic endothelium was measured based on DAF-FM fluorescent dye. NG-nitro-L-arginine methyl ester (L-NAME, 100 µM), an inhibitor of NOS, was used for control. (B) ROS generation was estimated in isolated mouse aorta using DHE fluorescent dye. MnTBAP (Manganese (III) Tetrakis (4-Benzoic Acid) Porphyrin, 10 µM), a superoxide scavenger, was used for control. Data are presented as the mean±SD from n=6 animals from each group. *p<0.01 vs. Young, †p<0.01 vs. Old.

• 

  Fig. 3 Arginase inhibition by Piceatannol administration alters eNOS phosphorylation and dimer stability.(A) Western blot and densitometric analysis of eNOS pSer1177 and arginase II in mouse aorta. (B) eNOS dimer blot and densitometric analysis. Data are presented as the mean±SD from n=6 animals from each group. *p<0.05 vs. Young, †p<0.05 vs. Old, ns, non-significant.

• 

  Fig. 4 Effects of arginase inhibition by Piceatannol administration on vessel reactivity.(A) Cumulative dose-response curve to acetylcholine (Ach) after pre-constriction by phenylephrine (PE, 10−3 M). (B) Cumulative dose-response curve to sodium nitroprusside (SNP) after pre-constriction by phenylephrine (10−3 M). (C) Cumulative dose-response curve to phenylephrine normalized to the maximum response to KCl (60 mM). (D) Constriction response to a soluble guanylyl cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10−5 M). Data are presented as the mean±SD from n=6 animals from each group. *p<0.05 vs. Young, †p<0.05 vs. Old, ns, non-significant.

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