Geniposide Alleviates Isoproterenol-Induced Cardiac Fibrosis Partially via SIRT1 Activation in vivo and in vitro

Abstract

Objective: Geniposide (GE) is a major component in the fruit of Gardenia jasminoides Ellis. Oxidative stress, endoplasmic reticulum (ER) stress, and canonical Smad3 pathway are implicated in the pathogenesis of cardiac fibrosis. We aim to investigate the protective roles of GE in isoproterenol (ISO)-induced cardiac fibrosis.Methods: ISO was used to induce cardiac fibrosis in male C57BL/6 mice. GE and the EX-527 were given for 2 weeks to detect the effects of GE on cardiac fibrosis. Levels of oxidative stress, ER stress, and Smad3 were evaluated by real time-PCR, Western blots, immunohistochemistry staining, immunofluorescence staining, and assay kits.Results: GE treatment alleviated cardiac dysfunction, fibrosis, and hypertrophy in mice response to ISO. Additionally, GE also suppressed the transformation of cardiac fibroblasts to myofibroblasts stimulated by transforming growth factor-β (TGF-β) in vitro. Mechanistically, GE inhibited the oxidative stress, ER stress, as well as Smad3 pathway activated by ISO or TGF-β. A selective antagonist of sirtuin 1 deacetylase (SIRT1), EX-527, partially counteracted the anti-fibrotic effect and weakened the inhibitory effect on the transformation of cardiac fibroblasts to myofibroblasts after the treatment of GE. Acetylated Smad3 (ac-Smad3), oxidative stress, as well as ER stress pathway were significantly enhanced after SIRT1 was blocked while phosphorylated Smad3 (P-Smad3) was not affected.Conclusion: GE could combat cardiac fibrosis in vivo and in vitro by inhibiting oxidative stress, ER stress, and ac-Smad3 in a SIRT1-dependent manner and suppressing P-Samd3 pathway independent of SIRT1 activation. GE is expected to be a promising agent against cardiac fibrosis.

Antioxidative Property and Molecular Mechanisms Underlying Geniposide-Mediated Therapeutic Effects in Diabetes Mellitus and Cardiovascular Disease

“…Sirtuin 1 deacetylase (SIRT1) is one of the mammalian homologs of the yeast silent information regulator 2 protein, which in essence is a nicotinamide adenine dinucleotide NAD(+)-dependent deacetylase [77]. A potent agonist of SIRT1, resveratrol, was found to inhibit the production of ROS in cardiomyocytes by activating SIRT1 and enhancing mitochondrial biogenesis [78]. Our previous study unveiled that geniposide could alleviate isoprenaline-induced cardiac dysfunction and fibrosis in the mouse model with cardiac fibrosis.…”

“…An in vitro experiment disclosed that geniposide also suppressed the transformation of cardiac fibroblasts into myofibroblasts stimulated by TGF- β . The mechanism of anti-cardiac fibrosis from geniposide is associated with the inhibition of the acetylated- (ac-) Smad3 pathway, oxidative stress, and ERS in a SIRT1-dependent manner; meanwhile, geniposide could also reduce phosphorylated- (p-) Smad3 level by inactivating the type II TGF- β receptor independent of SIRT1 activation [78] (Figure 5).…”

Geniposide protects PC12 cells from lipopolysaccharide-evoked inflammatory injury via up-regulation of miR-145-5p

“…Geniposide is an active ingredient of traditional Chinese herbal medicine Gardenia jasminoides Ellis, which is extensively applied in clinic to treat stroke in China. Geniposide has various pharmacological properties, such as anti-inflammatory, antidiabetic, anti-fibrotic, antioxidative, anti-apoptotic and antitumour activities [5][6][7][8][9]. Besides this, geniposide was revealed to be beneficial in suppressing Helicobacter pylori infections [10].…”

Nucleotide-Binding Oligomerization Domain-Like Receptor 3 Deficiency Attenuated Isoproterenol-Induced Cardiac Fibrosis via Reactive Oxygen Species/High Mobility Group Box 1 Protein Axis

“…021302) mice were obtained from the Jackson Laboratory. Mice were injected subcutaneously with ISO or equal volumes of saline for 14 days (10 mg/kg for 3 days and 5 mg/kg for 11 days) (Jiang et al, 2017;Li N. et al, 2018). The animals were randomly divided into four groups (12 per group): wild-type (WT)-Sham, KO-Sham, WT-ISO, and KO-ISO.…”