Boysenberry polyphenol inhibits endothelial dysfunction and improves vascular health.

Ryo Furuuchi,Yohko Yoshida,Ippei Shimizu,Masayoshi Suda,Yuka Hayashi,Masaaki Nakao,Goro Katsuumi,Ryutaro Ikegami,Takayuki Wakasugi,Tohru Minamino

doi:10.1371/journal.pone.0202051

Abstract

Endothelial cells have an important role in maintaining vascular homeostasis. Age-related disorders (including obesity, diabetes, and hypertension) or aging per se induce endothelial dysfunction that predisposes to the development of atherosclerosis. Polyphenols have been reported to suppress age-related endothelial cell disorders, but their role in vascular function is yet to be determined. We investigated the influence of boysenberry polyphenol on vascular health under metabolic stress in a murine model of dietary obesity. We found that administration of boysenberry polyphenol suppressed production of reactive oxygen species (ROS) and increased production of nitric oxide (NO) in the aorta. It has been reported that p53 induces cellular senescence and has a crucial role in age-related disorders, including heart failure and diabetes. Administration of boysenberry polyphenol significantly reduced the endothelial p53 level in the aorta and ameliorated endothelial cell dysfunction in iliac arteries under metabolic stress. Boysenberry polyphenol also reduced ROS and p53 levels in cultured human umbilical vein endothelial cells (HUVECs), while increasing NO production. Uncoupled endothelial nitric oxide synthase (eNOS monomer) is known to promote ROS production. We found that boysenberry polyphenol reduced eNOS monomer levels both in vivo and in vitro, along with an increase of eNOS dimerization. To investigate the components of boysenberry polyphenol mediating these favorable biological effects, we extracted the anthocyanin fractions. We found that anthocyanins contributed to suppression of ROS and p53, in association with increased NO production and eNOS dimerization. In an ex vivo study, anthocyanins promoted relaxation of iliac arteries from mice with dietary obesity. These findings indicate that boysenberry polyphenol and anthocyanins, a major component of this polyphenol, inhibit endothelial dysfunction and contribute to maintenance of vascular homeostasis.

Highlights

Aging leads to an increasing prevalence of age-related disorders, such as diabetes and heart failure
The nitric oxide (NO) level was reduced in the aortas of high fat diet (HFD) mice, while this change was ameliorated by boysenberry polyphenol (BP) (Fig 1C)
HFD mice showed a marked decrease of the endothelial nitric oxide synthase (eNOS) dimer/monomer ratio in the aorta, while this change was ameliorated by BP administration (Fig 1D)

Summary

Introduction

Aging leads to an increasing prevalence of age-related disorders, such as diabetes and heart failure. The changes of gene expression make these cells resistant to apoptosis and lead to secretion of pro-inflammatory molecules, contributing to the development of chronic inflammation and tissue remodeling [2]. Aging and lifestyle-related diseases induce vascular dysfunction, and increases the risk of cardiovascular disease [3, 4]. This is termed “vascular senescence” and is well recognized to promote cardiovascular disorders, including atherosclerosis [5] and systolic cardiac dysfunction [6, 7], as well as systemic metabolic disorders [8]. Senescent endothelial cells have been detected in atherosclerotic plaque Such senescent cells produce pro-inflammatory cytokines and promote the development of low grade sterile inflammation and tissue remodeling, contributing to increased susceptibility to atherosclerotic diseases

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Results

Conclusion