A Novel Arginase Inhibitor Derived from Scutellavia indica Restored Endothelial Function in ApoE-Null Mice Fed a High-Cholesterol Diet

Abstract

Elevated endothelial arginase activity decreases nitric oxide (NO) production by competing with the substrate L-arginine, previously reported, and reciprocally regulating endothelial nitric oxide synthase (eNOS) activity. Thus, arginase inhibitors may help treat vascular diseases associated with endothelial dysfunction. A screening of metabolites from medicinal plants revealed that (2S)-5,29,59-trihydroxy-7,8-dimethoxy flavanone (TDF) was a noncompetitive inhibitor of arginase. We investigated whether TDF reciprocally regulated endothelial NO production and its possible mechanism. TDF noncompetitively inhibited arginase I and II activity in a dose-dependent manner. TDF incubation decreased arginase activity and increased NO production in human umbilical vein endothelial cells and isolated mouse aortic vessels and reduced reactive oxygen species (ROS) generation in the endothelium of the latter. These TDFmediated effects were associated with increased eNOS phosphorylation and dimerization but not with changes in protein content. Endothelium-dependent vasorelaxant responses to acetylcholine (Ach) were significantly increased in TDF-incubated aortic rings and attenuated by incubation with soluble guanylyl cyclase inhibitor. Phenylephrine-induced vasoconstrictor responses were markedly attenuated in TDF-treated vessels from wild-type mice. In atherogenic-prone ApoE 2/2 mice, TDF attenuated the high-cholesterol diet (HCD)-induced increase in arginase activity, which was accompanied by restoration of NO production and reduction of ROS generation. TDF incubation induced eNOS dimerization and phosphorylation at Ser1177. In addition, TDF improved Ach-dependent vasorelaxation responses and attenuated U46619-dependent contractile responses but did not change sodium nitroprusside-induced vasorelaxation or N-NAME-induced vasoconstriction. The findings suggest that TDF may help treat cardiovascular diseases by reducing pathophysiology derived from HCD-mediated endothelial dysfunction.

Arginase II Contributes to the Ca 2+ /CaMKII/eNOS Axis by Regulating Ca 2+ Concentration Between the Cytosol and Mitochondria in a p32‐Dependent Manner

“…However, a novel mechanism showed that oxidized low‐density lipoprotein triggered translocation of arginase II from mitochondria to the cytoplasm via mitochondrial processing peptidase with a simultaneous increase in arginase activity that drove endothelial nitric oxide synthase (eNOS) uncoupling by depleting the substrate pool available for NO biosynthesis 17. Similarily, we also showed that an arginase inhibitor‐enhanced eNOS phosphorylation at Ser117718 and arginase II inhibition improved the loss of mitochondrial membrane potential by a Ca 2+ ‐dependent mechanism and prevented mitochondrial reactive oxygen species (ROS) production 19…”

Thirty Years of Saying NO

“…29,[101][102][103][104][105] Major causes of l-arginine steal in the blood vessel wall include increased ROS production and activation of Rho-kinase that stimulates both mitochondrial processing peptidase (promoting translocation of arginase from mitochondria to the cytosol and hence increasing its activity) and p38 mitogen-activated PK (phosphorylating transcription factors [activating transcription factor-2 and c-Jun] upregulating the expression and activity of the enzyme); conversely, inhibition of arginases improves endothelium-dependent, NO-mediated dilatations/ relaxations when they are impaired because of upregulation of these enzymes. [100][101][102][103][104][105][106][107][108][109] Another sink for l-arginine can be the induction of iNOS, which is minimally present under physiological conditions, but when expressed/present during infection, chronic inflammation, and in tumors, continuously produces large amounts of NO, thus competing with eNOS for the common substrate and accelerating S-nitrosylation of the enzyme ( Figure 5). …”

Cardiovascular Risk Factors and their Relationship with Endothelial Dysfunction in Rural and Urban South African Children

“…ADMA inhibits eNOS by competing with its substrate, L-arginine thereby impairing the production of NO [9]. Thus, decrease availability of NO as a result of obesity and increased ADMA leads to endothelial dysfunction [10]. Also, pro-in ammatory cytokines released from adipose tissue may lead to the generation of reactive oxygen species (ROS) [11].…”