Introduction
Doxorubicin-Induced Cardiotoxicity
Molecular Mechanisms of DOX-Induced Cardiotoxicity
AMPK
Structure and Function of AMPK
The Role of AMPK in DOX Cardiotoxicity
AMPK-Activating Agents and Their Role in DOX Cardioprotection
Overview of AMPK-Activating Agents
Compound | Mechanism of AMPK activation | Downstream effect mediating cardioprotection | Model system | Reference |
---|---|---|---|---|
Metformin | Decreased ATP to AMP ratio? ATP to AMP ratio–independent AMPKα1 phosphorylation? | Increased PDGFR expression and increased cell viability | Rat H9c2 cardiomyoblasts | [77] |
Decreased oxidative stress, prevention of PPARα-cyclophilin D interaction | Rat H9c2 cardiomyoblasts | [78] | ||
Via adiponectin receptor? | Decreases apoptosis | HL-1 mouse cardiomyocytes | [79] | |
Decreased apoptosis and fibrosis | C57BL/6 and APN-SE mice | [80] | ||
Resveratrol | Decreased ATP to AMP ratio? ATP to AMP ratio–independent AMPKα1 phosphorylation? | Decreased apoptosis and fibrosis | Wistar rats | [81] |
Decreased fibrosis via reduced TGFβ | F344 rats | [82] | ||
Sirtuin 1 activation and deacetylation of LKB1 leading to AMPKα1 phosphorylation | Decreased apoptosis | Rat H9c2 cardiomyoblasts | [83] | |
Decreased ATP to AMP ratio? ATP to AMP ratio–independent AMPKα1 phosphorylation? | Decreased apoptosis | Rat H9c2 cardiomyoblasts | [84] | |
Decreased apoptosis and increased autophagy via ULK1/mTOR | Rat H9c2 cardiomyoblasts | [85] | ||
Quercetin | Increased expression of AMPKα2 | Increased expression of PPARα and PCG-1α | Sprague–Dawley rats | [86] |
AICAR | AMP-mimetic (allosteric AMPK activation) | Decreased p53-mediated apoptosis | Mouse embryonic fibroblasts | [87] |
2-Deoxyglucose | Decreased ATP to AMP ratio | Decreased apoptosis and increased autophagy | Rat neonatal cardiomyocytes | [88] |
FGF21 | Via sirtuin 1 activation and deacetylation of LKB1 leading to AMPKα1 phosphorylation | Decreased apoptosis, inflammation and oxidative stress | Rat H9c2 cardiomyoblasts, adult mouse cardiomyocytes and 129S1/SyImJ mice | [89] |
Liraglutide | ? (GLP-1 agonist) | Reduced inflammation and necrosis via Akt signalling | Wistar rats | [90] |
Exenatide | ? (GLP-1 agonist) | Increased autophagy | Rat H9c2 cardiomyoblasts | [91] |
Melatonin | ? | Reduced mitochondrial oxidative stress and apoptosis, increased PGC1α expression | Rat H9c2 cardiomyoblasts and C57BL/6 mice | [92] |
Oleuropein | ? | Reduced apoptosis, oxidative stress and normalised protein synthesis | Wistar rats | [93] |
Aspalathin | ? | Decreased apoptosis and increased autophagy | Rat H9c2 cardiomyoblasts | [94] |