(−)-Epicatechin induces calcium and translocation independent eNOS activation in arterial endothelial cells

Ramírez-Sánchez, Israel; Maya, Lisandro; Ceballos, Guillermo; Villarreal, Francisco

doi:10.1152/ajpcell.00406.2010

Cited by 45 publications

(36 citation statements)

References 37 publications

(44 reference statements)

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“…In the case of exercise, the upstream triggering event is likely associated with mechanotransduction whereas that of Epi may involve the binding to receptors [13]. We and others have generated indirect evidence for the existence of Epi receptors.…”

Section: Discussionmentioning

confidence: 99%

“…It is well accepted that the activation of eNOS in the setting of myocardial ischemia can trigger cardioprotection [11] . In this regard, we have reported on the ability of Epi to acutely activate eNOS, stimulate the production of nitric oxide (NO) and trigger vasorelaxation related events in cultures of human coronary artery endothelial cells and in intact vessels [12, 13] . Thus, Epi induced activation of eNOS may partly explain the cardioprotective effects of the flavanol.…”

Section: Introductionmentioning

confidence: 99%

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Stimulatory Effects of the Flavanol (-)-Epicatechin on Cardiac Angiogenesis

Ramírez-Sánchez

Nogueira

Moreno

et al. 2012

Journal of Cardiovascular Pharmacology

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The consumption of moderate amounts of cocoa products has been associated with reductions in the incidence of cardiovascular diseases. In animal studies, the flavanol (-)-epicatechin (Epi) yields cardioprotection. The effects may be partly due to its capacity to stimulate endothelial nitric oxide synthase (eNOS). The sustained activation of eNOS as observed with exercise, can serve as a trigger of muscle angiogenesis via the activation of VEGF related events. Experiments were pursued to examine the potential of Epi to stimulate myocardial angiogenesis and determine the effects that its combined use with exercise (Ex) may trigger. Hearts obtained from a previous study were used for this purpose. Animals received 1 mg/kg of Epi or water (vehicle) via oral gavage (twice daily). Epi and/or Ex (by treadmill) was provided for 15 days. Results indicate that Ex or Epi significantly stimulate myocardial angiogenesis by ~30% above control levels. The use of Epi-Ex lead to further significant increases (to ~50%). Effects were associated with increases in protein levels and/or activation of canonical angiogenesis pathway associated events (HIF1α, VEGF, VEGFR2, PI3K, PDK, AKT, eNOS, NO, cGMP, MMP-2/-9, Src-1 and CD31). Thus, the use of Epi may represent a safe and novel means to stimulate myocardial angiogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Stimulatory Effects of the Flavanol (-)-Epicatechin on Cardiac Angiogenesis

Ramírez-Sánchez

Nogueira

Moreno

et al. 2012

Journal of Cardiovascular Pharmacology

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“…Thus, under Ca 2+ -free conditions, EPI stimulates NO synthesis independent of calmodulin binding to eNOS and of its translocation into the cytoplasm. We also examined the effect of EPI on the NO/cGMP/vasodilator-stimulated phosphoprotein pathway activation in isolated Ca 2+ -deprived canine mesenteric arteries [5]. Results demonstrated that under these conditions, EPI induces the activation of this vasorelaxation related pathway and that this effect can be inhibited by pretreatment with the eNOS inhibitor L-NG-nitroarginine methyl ester (L-NAME).…”

Section: Introductionmentioning

confidence: 99%

(-)-Epicatechin-induced calcium independent eNOS activation: roles of HSP90 and AKT

et al. 2012

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Cardiovascular disease (CVD) is a leading determinant of mortality and morbidity in the world. Epidemiologic studies suggest that flavonoid intake plays a role in the prevention of CVD. Consumption of cocoa products rich in flavonoids lowers blood pressure and improves endothelial function in healthy subjects as well as in subjects with vascular dysfunction such as smokers and diabetics. The vascular actions of cocoa follow the stimulation of nitric oxide (NO). These actions can be reproduced by the administration of the cocoa flavanol (−)-epicatechin (EPI). Previously, using human endothelial cells cultured in calcium-free media, we documented EPI effects on eNOS independently of its translocation from the plasmalemma. To further define the mechanisms behind EPI-eNOS activation in Ca2+ -deprived endothelial cells, we evaluated the effects of EPI on the eNOS/AKT/HSP90 signaling pathway. Results document an EPI-induced phosphorylation/activation of eNOS, AKT, and HSP90. We also demonstrate that EPI induces a partial AKT/HSP90 migration from the cytoplasm to the caveolar membrane fraction. Immunoprecipitation assays of caveolar fractions demonstrate a physical association between HSP90, AKT, and eNOS. Thus, under Ca2+-free conditions, EPI stimulates NO synthesis via the formation of an active complex between eNOS, AKT, and HSP90.

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“…Recently, Villarreal's research group (28,31,32,36,41,42) has examined the effects of epicatechin in the setting of cardiovascular disease. They showed that the beneficial effect of epicatechin could be due in part to protection of mitochondria (36).…”

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confidence: 99%

Epicatechin limits renal injury by mitochondrial protection in cisplatin nephropathy

Tanabe

Tamura

Lanaspa

et al. 2012

American Journal of Physiology-Renal Physiology

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Cisplatin nephropathy can be regarded as a mitochondrial disease. Intervention to halt such deleterious injury is under investigation. Recently, the flavanol (-)-epicatechin emerges as a novel compound to protect the cardiovascular system, owing in part to mitochondrial protection. Here, we have hypothesized that epicatechin prevents the progression of cisplatin-induced kidney injury by protecting mitochondria. Epicatechin was administered 8 h after cisplatin injury was induced in the mouse kidney. Cisplatin significantly induced renal dysfunction and tubular injury along with an increase in oxidative stress. Mitochondrial damages were also evident as a decrease in loss of mitochondrial mass with a reduction in the oxidative phosphorylation complexes and low levels of MnSOD. The renal damages and mitochondrial injuries were significantly prevented by epicatechin treatment. Consistent with these observations, an in vitro study using cultured mouse proximal tubular cells demonstrated that cisplatin-induced mitochondrial injury, as revealed by a decrease in mitochondrial succinate dehydrogenase activity, an induction of cytochrome c release, mitochondrial fragmentation, and a reduction in complex IV protein, was prevented by epicatechin. Such a protective effect of epicatechin might be attributed to decreased oxidative stress and reduced ERK activity. Finally, we confirmed that epicatechin did not perturb the anticancer effect of cisplatin in HeLa cells. In conclusion, epicatechin exhibits protective effects due in part to its ability to prevent the progression of mitochondrial injury in mouse cisplatin nephropathy. Epicatechin may be a novel option to treat renal disorders associated with mitochondrial dysfunction.

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(−)-Epicatechin induces calcium and translocation independent eNOS activation in arterial endothelial cells

Cited by 45 publications

References 37 publications

Stimulatory Effects of the Flavanol (-)-Epicatechin on Cardiac Angiogenesis

Stimulatory Effects of the Flavanol (-)-Epicatechin on Cardiac Angiogenesis

(-)-Epicatechin-induced calcium independent eNOS activation: roles of HSP90 and AKT

Epicatechin limits renal injury by mitochondrial protection in cisplatin nephropathy

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