Anti-fibrotic actions of Ghrelin by inhibition of the NADPH oxidase-ROS signaling pathway
CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY(2018)
Abstract
This study aims to investigate whether the molecular mechanisms by which Ghrelin inhibits cardiac fibrosis are linked to the NADPH oxidase-ROS signaling pathway. Adult male Sprague Dawley (SD) rats were randomly divided into 4 groups: sham, myocardial infarction (MI), MI + Ghrelin (100 mu g/kg, twice daily, subcutaneous for 4 weeks beginning 24 h post-MI), or Ghrelin alone. Adult rat cardiac fibroblasts (CFs) were isolated and pretreated with or without Ghrelin for 24 h, followed by stimulation with or without angiotensin II (Ang II) for another 24 h. Cardiac collagen deposition, hydroxyproline content, malondialdehyde (MDA) content, NADPH oxidase activity, reactive oxygen species (ROS) content, and NADPH oxidase-ROS pathway related proteins (SGK1, CTGF, MMP-2/9, and Collagen I/III) and the anti-oxidative stress proteins (Nrf2 and HO-1) were evaluated. Compared to sham rats, MI rats had increased collagen deposition, hydroxyproline content, MDA content, and ROS content in the non-infarcted LV (all p < 0.05). NADPH oxidase 4 (Nox4), SGK1, MMP-2 and 9, CTGF, and collagen I and III mRNA were all induced in the infarct region and attenuated with Ghrelin (all p < 0.05). In adult rat cardiac fibroblasts, SGK1, CTGF, MMP-2/9 and Collagen I/III expression were increased by Ang II stimulation, which were all attenuated by pre-treatment with Ghrelin, apocynin (a specific NADPH oxidase inhibitor), or tempol (a ROS scavenger; all p < 0.05). In addition, Ghrelin treatment increased Nrf2 and HO-1 expression and inhibited Nrf2 and HO-1 to counteract the effect of Ghrelin on NADPH oxidase-ROS signaling. In conclusion, Ghrelin reduced cardiac fibrosis in post-MI rats and Ang II-induced cardiac fibroblasts by inhibiting NADPH oxidase-ROS signaling.
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Key words
Ghrelin,cardiac fibrosis,NADPH oxidase,ROS,SGK1
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