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.
Highlights
Cardiac fibrosis is a common pathological feature in many cardiovascular diseases, involving hypertension, myocardial infarction, dilated cardiomyopathy, and diabetes mellitus (Gyöngyösi et al, 2017)
Accumulating evidence has shown that Sirtuin 1 deacetylase (SIRT1) may exert favorable cardiovascular protective effects by regulating oxidative stress, endoplasmic reticulum (ER) stress, and the TGF-β1/Smad3 pathway, which are crucial for the development of cardiac fibrosis (Alcendor et al, 2007; Cappetta et al, 2015; Guo et al, 2015)
To further explore the precise mechanisms contributing to the protective effect of GE, we subsequently measured the levels of protein markers associated with oxidative stress, ER stress, and the Smad3 pathway
Summary
Cardiac fibrosis is a common pathological feature in many cardiovascular diseases, involving hypertension, myocardial infarction, dilated cardiomyopathy, and diabetes mellitus (Gyöngyösi et al, 2017). The precise mechanisms regulating the process of cardiac fibrosis remain incompletely understood, but emerging evidence supports a critical role of the transforming growth factor-β (TGF-β)/Smad signaling pathway in cardiac fibrosis. Cardiac oxidative stress enhances cardiac collagen synthesis and inhibits collagen degradation in perivascular/interstitial fibrosis in hypertensive rats (Zhao et al, 2008) and provokes accumulation of ECM in the left ventricle (LV) of streptozotocin (STZ)-induced diabetic rats by activating several genes correlated with fibrosis, such as fibronectin, TGFβ1, and connective tissue growth factor (CTGF), in addition to activation of the NF-κB pathway (Aragno et al, 2008). Suppression of oxidative stress, ER stresses, and the TGF-β/Smad signaling pathway is regarded as a promising therapy for cardiac fibrosis (Ayala et al, 2012; Kassan et al, 2012)
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