Docosahexaenoic Acid-Enhanced Autophagic Flux Improves Cardiac Dysfunction after Myocardial Infarction by Targeting the AMPK/mTOR Signaling Pathway

Abstract

Background and Purpose. Docosahexaenoic acid (DHA) is a type of polyunsaturated fatty acid enriched in cod liver oil and seaweed. It is necessary for the human body and has important functions, such as antioxidation and antiatherosclerosis activities. Long-term oral administration of DHA or the use of DHA at the initial stage of ischemia can increase the level of autophagy and exert a protective effect on neurological functions related to cerebral infarction. However, the effect of DHA on myocardial injury and cardiac insufficiency after myocardial infarction (MI) is unknown. This study was aimed at exploring whether DHA plays a protective role in AMI and its specific molecular mechanism. Experimental Method. In vitro cardiomyocyte hypoxia and in vivo MI injury models were used to determine the role of DHA in MI. Hypoxic injury induced damage in cultured neonatal mouse cardiomyocytes (NMCs). The C57BL/6J mouse MI model was established by permanent ligation of the left anterior descending branch. Main Results. DHA improved the cardiomyocyte viability of NMCs induced by hypoxia injury and reduced cell necrosis. DHA reduced infarct size, improved heart function, and reduced the degree of myocardial fibrosis in mice after MI. In addition, DHA enhanced autophagy flux and reduced apoptosis in vitro and in vivo. In addition, we found that chloroquine, an autophagy inhibitor, blocked the protective effect of DHA on cardiomyocyte apoptosis and cardiac dysfunction, indicating that DHA exerts cardioprotective effects in part by promoting autophagy flux. We also observed that DHA enhanced autophagy flux by activating the AMPK/mTOR signaling pathway. Conclusions and Significance. In conclusion, our findings indicate for the first time that DHA improves MI-induced cardiac dysfunction by promoting AMPK/mTOR-mediated autophagic flux.

Metformin Alleviates Sepsis-Associated Myocardial Injury by Enhancing AMP-Activated Protein Kinase/Mammalian Target of Rapamycin Signaling Pathway–Mediated Autophagy

“…AMPK is a cellular energy sensor that regulates several cellular processes, including autophagy, and negatively regulates the downstream signaling molecule mTOR. 38 AMPK-activated autophagy plays an important role in myocardial infarction, 16 myocardial hypertrophy, 39 and sepsis-induced organ injury. 40 Metformin is a well-known activator of AMPK.…”

“…Subsequently, 10 mM compound C (HY-13418A; MCE) was administered 1 hour before LPS insult. 16 H9c2 cells were harvested after 24 hours of incubation, and further analysis was performed.…”

Docosahexaenoic acid reduced vascular endothelial cell injury in diabetic rats via the modulation of autophagy

“…In an experiment conducted by Shi and co-workers, they found that DHA can increase autophagic flux by the activation of LC3 and reduction of P62 levels in hypoxic mouse cardiomyocytes. 22 It is well-established that DHA stimulates the autophagy through p53mediated AMPK/mTOR signaling axis. 23 The activation of AMPK in bone marrow macrophages promotes the deactivation of Toxoplasma gondii via the fusion of the autophagosome with parasite-containing vacuoles.…”

“…It has been shown that docosahexaenoic acid (DHA), a natural omega-3 fatty acid, can exert therapeutic effects in several pathological conditions via the promotion of autophagic flux with simultaneous suppression of apoptotic changes. 11 DHA is extracted from algal oil with anti-inflammatory compounds like atherosclerosis. 12 This study was conducted to investigate the therapeutic effects of DHA on cardiovascular injury in D2M rats and its possible mechanism mediated via the autophagy signaling pathway (Figure 1).…”