ERK5/HDAC5-mediated, resveratrol-, and pterostilbene-induced expression of MnSOD in human endothelial cells.

Scope: Mitochondrial oxidative stress is closely correlated with numerous cardiovascular diseases. Manganese superoxide dismutase (MnSOD) is an important antioxidant enzyme in mitochondria. Although polyphenols can induce the expression of MnSOD, their corresponding mechanisms remains unclear. In this study, we tested the hypothesis that resveratrol and pterostilbene can activate the expression of MnSOD through an AMPK-ERK5/HDAC5-KLF2 pathway.

Methods And Results: Our results revealed that two stilbenes reduced mitochondrial superoxide-free radicals, and endothelial cell senescence, and increased the mRNA expression of several genes related to mitochondrial function, including MnSOD. Moreover, two stilbenes upregulated the activation of human MnSOD promoter luciferase reporter gene and protein level in human umbilical vein endothelial cells. Similarly, two stilbenes also stimulated LKB1, AMPKα, extracellular-signal related kinase 5 (ERK5) phosphorylation, and histone acetylase 5 (HDAC5) and Kruppel-like factor 2 (KLF2) expression. The knockdown of AMP-activated protein kinase (AMPK), ERK5, and HDAC5 by using short-hairpin RNA blocked pterostilbene-induced phosphorylation of their downstream signaling proteins and the expression of KLF2. Furthermore, using a chromatin immunoprecipitation-PCR detection method, we found that resveratrol and pterostilbene promoted KLF2 binding to CACCC sites of the human MnSOD promoter.

Conclusion: Resveratrol and pterostilbene can activate MnSOD expression through ERK5/HDAC5 pathway, thus alleviating mitochondrial oxidative stress in endothelial cells that relates to cardiovascular disease.