| First Author | Wang Q | Year | 2014 |
| Journal | Toxicol Sci | Volume | 142 |
| Issue | 1 | Pages | 6-20 |
| PubMed ID | 25092649 | Mgi Jnum | J:224342 |
| Mgi Id | MGI:5662042 | Doi | 10.1093/toxsci/kfu158 |
| Citation | Wang Q, et al. (2014) AMP-activated protein kinase deficiency rescues paraquat-induced cardiac contractile dysfunction through an autophagy-dependent mechanism. Toxicol Sci 142(1):6-20 |
| abstractText | AIM: Paraquat, a quaternary nitrogen herbicide, is a highly toxic prooxidant resulting in multi-organ failure including the heart although the underlying mechanism still remains elusive. This study was designed to examine the role of the cellular fuel sensor AMP-activated protein kinase (AMPK) in paraquat-induced cardiac contractile and mitochondrial injury. RESULTS: Wild-type and transgenic mice with overexpression of a mutant AMPK alpha2 subunit (kinase dead, KD), with reduced activity in both alpha1 and alpha2 subunits, were administered with paraquat (45 mg/kg) for 48 h. Paraquat elicited cardiac mechanical anomalies including compromised echocardiographic parameters (elevated left ventricular end-systolic diameter and reduced factional shortening), suppressed cardiomyocyte contractile function, intracellular Ca(2+) handling, reduced cell survival, and overt mitochondrial damage (loss in mitochondrial membrane potential). In addition, paraquat treatment promoted phosphorylation of AMPK and autophagy. Interestingly, deficiency in AMPK attenuated paraquat-induced cardiac contractile and intracellular Ca(2+) derangement. The beneficial effect of AMPK inhibition was associated with inhibition of the AMPK-TSC-mTOR-ULK1 signaling cascade. In vitro study revealed that inhibitors for AMPK and autophagy attenuated paraquat-induced cardiomyocyte contractile dysfunction. CONCLUSION: Taken together, our findings revealed that AMPK may mediate paraquat-induced myocardial anomalies possibly by regulating the AMPK/mTOR-dependent autophagy. |
