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TNF-α is implicated in cardiac insulin resistance which is a critical risk factor for cardiac failure. Ginsenoside Rd, a purified component of the saponins found in P. notoginseng, has long been used for the treatment of cardiovascular diseases, inflammation, trauma, and internal and external bleeding due to injury. In this study, we reported that the effects of ginsenoside Rd on TNF-α-induced insulin resistance in cardiac cells and demonstrate the underlying mechanisms.
Chronic treatment of HL-1 adult cardiomyocyte with TNF-α led to insulin resistance, reflected by a significant inhibition of insulin-induced glucose uptake. This was associated with the extracellular signal-related kinase (ERK) signaling. We analyzed the effects of ginsenoside Rd on TNF-α induced cardiac insulin resistance with or without U0126 and LY294002 treatment using glucose uptake assay. Western blot was used to detect the impact of ginsenoside Rd on change of ERK signaling under TNF-α treatment with or without U0126 treatment. We accessed the involved mechanisms of ginsenoside Rd on HL-1 adult cardiomyocyte by knocking down and overexpressiong Nrf2 along with western blot and immunofluorescence.
Our results showed that ginsenoside Rd significantly improved TNF-α-induced insulin resistance in cardiac cells. Further study revealed that the effects of ginsenoside Rd on cardiac insulin resistance induced by TNF-α was through ERK signaling with followed by Nrf2 activation. Ginsenoside Rd further enhanced insulin sensitivity and attenuated TNF-α-induced insulin resistance under treatment ERK inhibitor U0126. Moreover, forced activation of Nrf2 by adenoviral overexpression of Nrf2 or knockdown of Nrf2 by Nrf2 siRNA promoted or proved the ERK activity inhibition under ginsenoside Rd treatment and recovered the blunted insulin sensitivity on glucose uptake in cardiomyocytes that were chronically treated with TNF-α. Upregulated of Nrf2 by its activator, D404, in cardiomyocytes acted synergistically with ginsenoside Rd preventing TNF-α induced ERK activation and insulin-signaling downregulation.
Ginsenoside Rd proved cardiomyocytes insulin resistance under TNF-α treatment and ERK mediated upregulation of Nrf2 activity was involved in the effects of ginsenoside Rd on TNF-α-induced insulin resistance.