Grape Seed Proanthocyanidin Extracts Enhance Endothelial Nitric Oxide Synthase Expression through 5′-AMP Activated Protein Kinase/Surtuin 1–Krüpple Like Factor 2 Pathway and Modulate Blood Pressure in Ouabain Induced Hypertensive Rats

Abstract

Grape seed proanthocyanidin extracts (GSPE) belonging to polyphenols, possess various biological effects including anti-inflammation, anti-oxidant, anti-aging, anti-atherosclerosis, etc. GSPE is potential in regulating endothelial function. However, the underlying mechanism is not clear yet. In this study, by small interfering RNA (siRNA) knocking down, we proved that GSPE increase endothelial nitric oxide synthase (eNOS) expression in human umbilical vessel cells (HUVECs) in vitro, which was attributed to its transcription factor Krüpple like factor 2 (KLF2) induction. Furthermore, GSPE activate 5′-AMP activated protein kinase (AMPK) and increase surtuin 1 (SIRT1) protein level, critical for KLF2 induction. We also illuminated the role of GSPE in hypertension treatment. By chronic administration of GSPE in ouabain induced hypertensive rats model, we access the effect of GSPE on blood pressure regulation and the possible mechanisms involved. After 5 weeks feeding, GSPE significantly block the ouabain induced blood pressure increase. The aortic NO production impaired by ouabain was improved. In conclusion, GSPE increase eNOS expression and NO production in an AMPK/SIRT1 dependent manner through KLF2 induction, and attenuate ouabain induced hypertension.Key words grape seed proanthocyanidin; endothelial nitric oxide synthase; hypertension; Krüpple like factor 2 Grape seed proanthocyanidin extracts (GSPE), belonging to polyphenols, is a potent antioxidant extracted from grape seeds and skins. The superoxide anion scavenging activity of GSPE was stronger than vitamin C, vitamin E or any other antioxidant.

Regulation of vascular endothelial genes by dietary flavonoids: structure-expression relationship studies and the role of the transcription factor KLF-2

“…Moreover, luteolin and apigenin up-regulation of KLF-2 gene expression was statistically significant. An increment of KLF-2 expression in HUVECs by resveratrol [44] and also by a grape seed extract [45] has been previously shown, but as far as we know, this is the first time that an induction of KLF-2 expression by some flavonoids is reported. However, additional studies would be necessaries to know flavonoid effect on DNA binding activity of KLF-2 or whether it actually translocated to the nucleus.…”

Proanthocyanidin Protects Human Embryo Hepatocytes from Fluoride-Induced Oxidative Stress by Regulating Iron Metabolism

“…Previous studies revealed that the antioxidant capacity of GSPE is higher than that of vitamin E and C [23,24]. It is believed GSPE induces antioxidant effects through several mechanisms, including neutralization of free radicals, reduction of peroxide concentrations, and repair of oxidized membranes, all of which alleviate oxidative damage [25][26][27]. Besides, GSPE shows little toxicity.…”

How Does Colistin-Induced Nephropathy Develop and Can It Be Treated?

“…The finding that levels of TOS and OSI, oxidative damage markers, and the AI, an apoptosis marker, were significantly lower in the colistinϩGSPE group than in the colistin group in this study suggests that GSPE establishes a renoprotective effect by reducing oxidative and apoptotic damage. Cui et al achieved significant increases in iNOS levels at the NO level with the administration of GSPE to rats over a 5-week period and showed that this had a pronounced antihypertensive effect (22). Additionally, increased iNOS expression is known to be associated with apoptotic damage (17).…”