Resveratrol induces nuclear factor-κB activity in human cardiac cells

Abstract

Background: Resveratrol is a grape polyphenol that prevents cardiac hypertrophy and protects the heart from ischemic injury, metabolic dysregulation, and inflammatory processes in several murine models.

Methods and results: The aim of this study was to investigate the effects of resveratrol on the inflammatory processes in human cardiac AC16 cells in order to gain a better understanding of its cardioprotective mechanisms in the human heart. Resveratrol induced the DNA-binding activity of the pro-inflammatory transcription factor NF-κB in AC16 cells, and exacerbated the increase caused by tumor necrosis factor-α (TNF-α). In accordance with this, resveratrol increased the expression of the pro-inflammatory genes ICAM-1 (intercellular adhesion molecule-1) and TNF-α. In contrast, resveratrol decreased the expression of pro-inflammatory genes IL-6 (interleukin-6) and MCP-1 (monocyte chemoattractant protein-1). Likewise, resveratrol also induced inflammation in rat neonatal cardiomyocytes, and in the heart of mice fed a standard chow diet supplemented with resveratrol (1g/kg diet) for four months. Western-blot analyses revealed that NF-κB p65 subunit levels were upregulated in an IκB-dependent manner in the nuclei of resveratrol-treated human cardiac cells. Finally, resveratrol activated the signal transducer and activator of transcription 3 (STAT3) signaling and induced the expression of its anti-apoptotic downstream effector Bcl-xL, both involved in the cardioprotective survival activating factor enhancement (SAFE) pathway.

Conclusions: Resveratrol enhanced NF-κB activity in human and murine cardiac cells, in a process that coincided with the activation of STAT3 and anti-apoptotic downstream effectors. Therefore, activation of the SAFE pathway by resveratrol might be involved in the cardioprotective effects of this compound.

Keywords: AMP-activated protein kinase; AMPK; Cardiovascular disease; EMSA; HAT; HDAC; Heart; ICAM-1; IKKα; IL-6; Inflammation; IκBα kinase; MCP-1; NF-κB; Resveratrol; SAFE; SOCS; STAT3; TNF-α; electrophoretic mobility shift assay; histone acetyltransferase; histone deacetylase; intercellular adhesion molecule-1; interleukin 6; monocyte chemoattractant protein-1; nuclear factor-κB; signal transducer and activator of transcription 3; suppressor of cytokine signaling; survival activating factor enhancement; tumor necrosis factor-α.