Aspirin alleviates cardiac fibrosis in mice by inhibiting autophagy

Abstract

Aspirin (ASA) is a cardioprotective drug with anti-cardiac fibrosis action in vivo. This study was aimed to clarify the anti-cardiac fibrosis action of ASA and the underlying mechanisms. Two heart injury models (injection of isoproterenol and ligation of the left anterior descending branch) were used in mice to induce cardiac fibrosis. The animals were treated with ASA (10 mg·kg -1 ·d -1, ig) for 21 and 14 d, respectively. ASA administration significantly improved cardiac function, and ameliorated heart damage and fibrosis in the mice. The mechanisms underlying ASA's anti-fibrotic effect were further analyzed in neonatal cardiac fibroblasts (CFs) exposed to hypoxia in vitro. ASA (0.5-5 mmol/L) dose-dependently inhibited the proliferation and Akt phosphorylation in the CFs. In addition, ASA significantly inhibited CF apoptosis, and decreased the levels of apoptosis markers (cleaved caspase 3 and Parp1), which might serve as a side effect of anti-fibrotic effect of ASA. Furthermore, ASA dose-dependently inhibited the autophagy in the CFs, as evidenced by the reduced levels of autophagy marker LC3-II. The autophagy inhibitor Pepstatin A (PepA) promoted the inhibitory effect of ASA on CF proliferation, whereas the autophagy inducer rapamycin rescued ASA-caused inhibition of CF proliferation, suggesting an autophagydependent anti-proliferative effect of ASA. Both p38 inhibitor SB203580 and ROS scavenger N-acetyl-cysteine (NAC) significantly decreased Akt phosphorylation in CFs in the basal and hypoxic situations, but they both significantly increased LC3-II levels in the CFs. Our results suggest that an autophagy-and p38/ROS-dependent pathway mediates the anti-cardiac fibrosis effect of ASA in CFs. As PepA and SB203580 did not affect ASA-caused inhibition of CF apoptosis, the drug combination will enhance ASA's therapeutic effects.

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

“…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). In a rat liver fibrosis model, aspirin improved the degree of liver fibrosis in a dose-dependent manner (21), but the underlying molecular mechanism remains unclear.…”

“…A recent study in a rat liver fibrosis model demonstrated that aspirin may significantly improve the degree of liver fibrosis in rats (21). In addition, aspirin has a positive effect on improving cardiac fibrosis (22). A recent study has demonstrated that aspirin has a positive effect on the growth and repair of the endometrium following IUAs (23), suggesting that this may be associated with the promotion…”

Caloric Restriction Mimetics against Age-Associated Disease: Targets, Mechanisms, and Therapeutic Potential

“…Aspirin also reduces mTOR signaling and activates AMPK and autophagy in colorectal cancer (CRC) cells (Din et al, 2012), which might explain its anti-cancer efficacy. However, contradictory results were reported on cardiac fibroblasts, in which it inhibited autophagy (Liu et al, 2017b). AMPK activation was also found in vivo in mice (Hawley et al, 2012) and might represent a major mechanism of aspirin-triggered CRM effects.…”

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

“…We found that aspirin attenuates the collagen production induced by Ang II in cultured cardiac fibroblasts. This result was supported by the finding that aspirin significantly inhibited CF apoptosis and decreased the levels of apoptosis markers [26]. Ang II also contributes to ongoing inflammation and stimulates the tyrosine phosphorylation of the linker protein SHC, causing Ras activation.…”