Aspirin Reduces Cardiac Interstitial Fibrosis by Inhibiting Erk1/2-Serpine2 and P-Akt Signalling Pathways

Abstract

Background/Aims: Cardiac interstitial fibrosis is an abnormality of various cardiovascular diseases, including myocardial infarction, hypertrophy, and atrial fibrillation, and it can ultimately lead to heart failure. However, there is a lack of practical therapeutic approaches to treat fibrosis and reverse the damage to the heart. The purpose of this study was to investigate the effect of long-term aspirin administration on pressure overload–induced cardiac fibrosis in mice and reveal the underlying mechanisms of aspirin treatment. Methods: C57BL/6 mice were subjected to transverse aortic constriction (TAC), and treated with 10 mg·kg^-1·day^-1 of aspirin for 4 weeks. Masson staining and a collagen content assay were used to detect the effects of aspirin on cardiac fibrosis in vivo and in vitro. Western blot and qRT-PCR were applied to examine the impact of aspirin on extracellular signal-regulated kinases (Erks), p-Akt/β-catenin, SerpinE2, collagen I, and collagen III levels in the mice heart. Results: Aspirin significantly suppressed the expression of α-smooth muscle actin (α-SMA; 1.19±0.19-fold) and collagen I (0.95±0.09-fold) in TAC mice. Aspirin, at doses of 100 and 1000 µM, also significantly suppressed angiotensin II-induced α-SMA and collagen I in cultured CFs. The enhanced phosphorylation of Erk1/2 caused by TAC (p-Erk1, 1.49±0.19-fold; p-Erk2, 1.96±0.68-fold) was suppressed by aspirin (p-Erk1, 1.04±0.15-fold; p-Erk2, 0.87±0.06-fold). SerpinE2 levels were suppressed via the Erk1/2 signalling pathway following treatment with aspirin (1.36±0.12-fold for TAC; 1.06±0.07-fold for aspirin+TAC). The p-Akt and β-catenin levels were also significantly inhibited in vivo and in vitro. Conclusions: Our study reveals a novel mechanism by which aspirin alleviates pressure overload-induced cardiac interstitial fibrosis in TAC mice by suppressing the p-Erk1/2 and p-Akt/β-catenin signalling pathways.

Repurposing mesalazine against cardiac fibrosis in vitro

“…Also, ERK1/2 inhibition attenuated fibrotic remodeling after myocardial infarction (Luo et al 2017 ). Although the structurally similar aspirin has been shown to suppress ERK1/2 and SMAD2/3 signaling (Li et al 2018 ; Zhang et al 2020 ), systemic side effects might overshadow the potential benefits. For this reason, we explored the effects of mesalazine on SMAD2/3 and ERK1/2 activation.…”

“…This is particularly interesting, since NFκ B has been shown to induce myofibroblast differentiation and fibrosis in pulmonary and hepatic fibrosis (Luedde and Schwabe 2011; Dong and Ma 2019). SMAD2/3 and ERK1/2 activation by TGFβ are central mechanisms of the fibrotic signaling cascade (Khalil et al 2017;Khalil et al 2017;Luo et al 2017) and modulation of these pathways has been proposed to affect cardiac and non-cardiac fibrosis (Rosenbloom et al 2013;Cheng et al 2016;Khalil et al 2017;Li et al 2018). In a murine model of pressure overload, selective block of SMAD2/3 signaling drastically attenuated fibrosis (Khalil et al 2017).…”

The Protective Effect of Aspirin against Myocardial Hypertrophy in Rats

“…Aspirin can reduce cardiac interstitial fibrosis by inhibiting Erk1/2-Serpine2 and P-Akt signaling pathways [20]. In humans, there is evidence that aspirin may impair reverse myocardial remodeling in heart failure patients treated with beta blockers [21].…”

Aspirin inhibits endometrial fibrosis by suppressing the�TGF‑β1‑Smad2/Smad3 pathway in intrauterine adhesions

“…Although there are some studies on the application of aspirin as an anti-fibrosis treatment, the specific anti-fibrosis mechanism of aspirin remains unclear. Aspirin decreases cardiac interstitial fibrosis caused by pressure overload in transverse aortic constriction (TAc) mice, which may be associated with the inhibition of the p-Erk1/2 and p-Akt/β-catenin signalling pathways by aspirin, thereby decreasing the expression levels of α-SMA and collagen I (37). A previous study revealed that aspirin alleviated cardiac fibrosis in mice by inhibiting autophagy (22).…”