Induction of Nur77 by hyperoside inhibits vascular smooth muscle cell proliferation and neointimal formation

Abstract

Nur77 is an orphan nuclear receptor that belongs to the nuclear receptor 4A (NR4A) subfamily, which has been implicated in a variety of biological events, such as cell apoptosis, proliferation, inflammation, and metabolism. Activation of Nur77 has recently been shown to be beneficial for the treatment of cardiovascular and metabolic diseases. The purpose of this study is to identify novel natural Nur77 activators and investigate their roles in preventing vascular diseases. By measuring Nur77 expression using quantitative RT-PCR, we screened active ingredients extracted from Chinese herb medicines with beneficial cardiovascular effects. Hyperoside (quercetin 3-D-galactoside) was identified as one of the potent activators for inducing Nur77 expression and activating its transcriptional activity in vascular smooth muscle cells (VSMCs). We demonstrated that hyperoside, in a time and dose dependent manner, markedly increased the expression of Nur77 in rat VSMCs, with an EC50 of ∼0.83μM. Mechanistically, we found that hyperoside significantly increased the phosphorylation of ERK1/2 MAP kinase and its downstream target cAMP response element-binding protein (CREB), both of which contributed to the hyperoside-induced Nur77 expression in rat VSMCs. Moreover, through activation of Nur77 receptor, hyperoside markedly inhibited both vascular smooth muscle cell proliferation in vitro and the carotid artery ligation–induced neointimal formation in vivo. These findings demonstrate that hyperoside is a potent natural activator of Nur77 receptor, which can be potentially used for prevention and treatment of occlusive vascular diseases.

Short-term UV-B radiation effects on morphology, physiological traits and accumulation of bioactive compounds in Prunella vulgaris L.

“…Hyperoside is a major bioactive compound in P. vulgaris spicas (Kim et al 2014) and exhibits a variety of biological activities, such as anticancer, anti-inflammatory, antioxidant and cardiovascular protective effects (Choi et al 2011;Kim et al 2011;Huo et al 2014;Liu et al 2016). In this study, UV-B radiation increased hyperoside accumulation in P. vulgaris spicas.…”

Effects of Fengliao-Changweikang in Diarrhea-predominant Irritable Bowel Syndrome Rats and Its Mechanism Involving Colonic Motility

“…This hypothesized pathway was supported by modern researches, some ingredients of FLCWK regulated smooth muscle by similar mechanisms, such as rutin and quercetin inhibiting the smooth muscle via the NO signaling pathways. [46][47][48][49][50] Similarly, K + channels also play a major role in the curative mechanism of FLCWK for IBS-D. The diversity of K + channels described in GI smooth muscles mainly includes voltage-gated K + channels, K A channels, calcium-activated K + channels, and ATPsensitive K + channels.…”

Pharmacological activities and pharmacokinetic study of hyperoside: A short review

“…It has also been reported that hyperoside protects cardiomyocytes from oxidative stress caused by ischemia and perfusion through significant upregulation of extracellular signal-regulated protein kinase (ERK) [36]. Hyperoside inhibited vascular lesions produced in a carotid artery ligation rat model [37]. It also possesses anticoagulant effects, as demonstrated through its capacity to restrain the production of thrombin and activated factor X (FXa), and extension of activated partial thromboplastin time (aPTT) and prothrombin time (PT) as well as inhibition of thrombin and FXa in HUVECs [13].…”