Ligustrazine and liguzinediol protect against doxorubicin‐induced cardiomyocytes injury by inhibiting mitochondrial apoptosis and autophagy

Abstract

Preventing or treating heart failure (HF) by blocking cardiomyocyte apoptosis is an effective strategy that improves survival and reduces ventricular remodelling and dysfunction in the chronic stage. Autophagy is a mechanism that degrades intracellular components and compensates for energy deficiency, which is commonly observed in cardiomyocytes of failed hearts. Cardiomyocytes activated by doxorubicin (DOX) exhibit strong autophagy. This study aims to investigate the potential protective effect of ligustrazine and its derivative liguzinediol on regulating DOX‐induced cardiomyocyte apoptosis and explore the use of the embryonic rat heart‐derived myoblast cell line H9C2 for identifying novel treatments for HF. The results indicated that it has been demonstrated to reverse myocardial infarction remodelling in failed hearts by promoting autophagy in salvaged cardiomyocytes and anti‐apoptosis of cardiomyocytes in granulation tissue. Our study suggests that ligustrazine and liguzinediol can be a promising agents and autophagy is potential pathway in the management of HF.

Liguzinediol potentiates the metabolic remodeling by activating the AMPK/SIRT3 pathway and represses Caspase-3/GSDME-mediated pyroptosis to ameliorate cardiotoxicity

“…In this study, we illustrated that DOX treatment not only diminished the viability of H9C2 cells but also heightened cardiomyocyte apoptosis. However, co-treatment with Lig effectively reversed the myocardial damage, aligning with our previous research [ 20 ]. The findings indicate that Lig enhances DOX-induced cardiac function by elevating LVFS and LVEF in vivo.…”

“…and the main cause of cardiac tissue loss and cardiac insufficiency during mitochondria-dependent intrinsic apoptosis [ 36 ]. Studies have reported that Lig has a myocardial protective effect on apoptosis under various pathogenic conditions [ 19 , 20 ]. To assess DOX-induced cardiomyocyte apoptosis, we conducted an immunofluorescence assay and examined apoptotic protein levels.…”

“…Previous studies from our research team have unveiled Lig’s ability to induce myotonic effects on normal isolated rat hearts, along with its potential to restore impaired cardiac contractility [ 18 ]. Notably, Lig has demonstrated efficacy in reducing myocardial cell apoptosis in stress-induced heart failure and promoting autophagy in salvaged cardiomyocytes [ 19 , 20 ]. Building on these findings, our current investigation seeks to establish a heart failure model induced by DOX to scrutinize Lig’s protective effects against oxidative stress.…”

Activation of AMPK/mTOR-Driven Autophagy and Suppression of the HMGB1/TLR4 Pathway with Pentoxifylline Attenuates Doxorubicin-Induced Hepatic Injury in Rats

“…In perspective, the “autophagy flux” can be described as a self-degrading process that involves the sequestration of damaged organelles/proteins into double-membraned autophagosomes that fuse with lysosomes for degradation by resident hydrolases [ 9 ]. In the context of DOX-induced organ toxicity, contradictory findings have emerged regarding autophagy events where both autophagy stimulation [ 10 , 11 ] and inhibition [ 1 , 12 , 13 ] have been described. In rodents, autophagy dysregulation has been implicated in mediating tissue damage [ 1 ].…”

“…Likewise, the upstream regulatory signals responsible for driving the autophagy events, such as the mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK), are deregulated by DOX, resulting in marked toxicity [ 1 , 9 ]. On the other hand, the literature revealed that autophagy stimulation can mediate DOX-induced toxicity [ 10 , 11 ]. Hence, further research is needed to determine how autophagy contributes to the toxicity associated with DOX.…”