The cardioprotective effects of (-)-Epicatechin are mediated through arginase activity inhibition in a murine model of ischemia/reperfusion

Ortiz-Vilchis, Pilar; Ortiz-Flores, Miguel; Pacheco, M González; Ramírez-Sánchez, Israel; Moreno‐Ulloa, Aldo; Vega, Lourdes; Ortiz, Alicia; Villarreal, Francisco; Rubio-Gayosso, Iván; Nájera, Nayelli; Meaney, Eduardo; Ceballos, Guillermo

doi:10.1016/j.ejphar.2017.11.007

Cited by 22 publications

(12 citation statements)

References 33 publications

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“…Flavonoids, such as catechin, 26,28) epigallocatechin gallate, 29,30) taxifolin, 31) and proanthocyanidin, 32) exert protective effects against I/R injury in the heart, brain, kidney, and liver. On the other hand, the main constituents of GE used in the present study are OPCs, which represent approximately 70% of all components.…”

Section: Discussionmentioning

confidence: 99%

Preventive Effects of Grape Extract on Ischemia/Reperfusion-Induced Acute Kidney Injury in Mice

Ohkita

Hayashi

Ito

et al. 2019

Biological & Pharmaceutical Bulletin

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Since grape extract (GE) contains oligomeric proanthocyanidins and numerous polyphenols, dietary GE supplements may exert protective effects against various diseases. The present study investigated the pharmacological effects of GE derived from Chardonnay in vitro and in vivo. GE (100 µg/mL) completely inhibited tumor necrosis factor-α-induced endothelin-1, monocyte chemoattractant protein-1, interleukin-1β, and intercellular adhesion molecule-1 gene expression in cultured endothelial cells. GE also strongly stimulated the phosphatidylinositol 3-kinase (PI3K)/Akt/endothelial nitric oxide synthase (eNOS) pathway. In the in vivo study, the effects of GE on ischemic acute kidney injury (AKI) were examined using male C57bl/6J wild-type and eNOS / mice. Right nephrectomized mice were exposed to 45 min of ischemia in the left kidney and this was followed by reperfusion. Although renal functional parameters in AKI mice significantly increased 48 h after reperfusion, the administration of GE (0.1 and 1 mg/kg, intravenous (i.v.)) 5 min before ischemia dosedependently improved post-ischemic renal dysfunction in wild-type mice. Renal histopathological studies on AKI mice revealed tubular necrosis, proteinaceous casts in tubuli, and medullary congestion. The administration of GE ameliorated this damage in wild-type mice, but not in eNOS / mice. Furthermore, GE significantly restored decreases in the renal nitric oxide metabolite content due to ischemia in wild-type mice, but not in eNOS / mice. Thus, eNOS is closely involved in the renoprotective effects of GE, strongly suggesting that GE supplements are useful as a prophylactic treatment for the development of ischemic AKI.

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Section: Discussionmentioning

confidence: 99%

Preventive Effects of Grape Extract on Ischemia/Reperfusion-Induced Acute Kidney Injury in Mice

Ohkita

Hayashi

Ito

et al. 2019

Biological & Pharmaceutical Bulletin

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“…The docking was performed in AutoDock Vina, with the coordinate of origin at x = 2.017, y = − 7.457 and z = − 0.116. The box size was set at x = 70, y = 70 and z = 70 ( Ortiz-vilchis et al, 2018 ).…”

Section: Methodsmentioning

confidence: 99%

“…Ar hydrolyzes L-arginine regulating NOS by substrate depletion ( Berkowitz et al, 2003 ). In addition, there is evidence of increased Ar activity due to OS-induced S-nitrosylation ( Ming et al, 2009 ; Ortiz-vilchis et al, 2018 ; Pernow and Jung, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, compounds that increase NO availability (i.e. NO donors, Ar I and Ar II inhibitors) have been shown to protect against EnD ( Berkowitz et al, 2003 ) and ischemia/reperfusion (I/R) injury ( Ortiz-vilchis et al, 2018 ). Flavonoids, particularly (−)-epicatechin (Epi), the most abundant flavanol in cacao, has been reported to inhibit Ar activity in rat kidney, human erythrocyte and in cultured endothelial cells thus, increasing NO production ( Schnorr et al, 2008 ).…”

Section: Introductionmentioning

confidence: 99%

“…Flavonoids, particularly (−)-epicatechin (Epi), the most abundant flavanol in cacao, has been reported to inhibit Ar activity in rat kidney, human erythrocyte and in cultured endothelial cells thus, increasing NO production ( Schnorr et al, 2008 ). In the setting of myocardial ischemia/reperfusion injury, we have demonstrated that Epi decreases Ar activity, maintaining eNOS function and reducing infarct size ( Ortiz-vilchis et al, 2018 ). We have also reported on the capacity of Epi to stimulate the production of NO and eNOS protein activation in aged endothelial cells ( Ramirez-Sanchez et al, 2010 ).…”

Section: Introductionmentioning

confidence: 99%

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Arginase inhibition by (−)-Epicatechin reverses endothelial cell aging

Garate‐Carrillo

Navarrete‐Yanez

Ortiz-Vilchis

et al. 2020

European Journal of Pharmacology

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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.

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Ameliorative influence of Garcinia kola seed extracts against multiple organ toxicity in monosodium glutamate-administered Wistar rats

et al. 2022

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The cardioprotective effects of (-)-Epicatechin are mediated through arginase activity inhibition in a murine model of ischemia/reperfusion

Cited by 22 publications

References 33 publications

Preventive Effects of Grape Extract on Ischemia/Reperfusion-Induced Acute Kidney Injury in Mice

Preventive Effects of Grape Extract on Ischemia/Reperfusion-Induced Acute Kidney Injury in Mice

Arginase inhibition by (−)-Epicatechin reverses endothelial cell aging

Ameliorative influence of Garcinia kola seed extracts against multiple organ toxicity in monosodium glutamate-administered Wistar rats

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