MDMA induces cardiac contractile dysfunction through autophagy upregulation and lysosome destabilization in rats

Abstract

The underlying mechanisms of cardiotoxicity of 3,4-methylenedioxymethylamphetamine (MDMA, "ecstasy") abuse are unclear. Autophagy exerts either adaptive or maladaptive effects on cardiac function in various pathological settings, but nothing is known on the role of autophagy in the MDMA cardiotoxicity. Here, we investigated the mechanism through which autophagy may be involved in MDMA-induced cardiac contractile dysfunction. Rats were injected intraperitoneally with MDMA (20mg/kg) or saline. Left ventricular (LV) echocardiography and LV pressure measurement demonstrated reduction of LV systolic contractility 24h after MDMA administration. Western blot analysis showed a time-dependent increase in the levels of microtubule-associated protein light chain 3-II (LC3-II) and cathepsin-D after MDMA administration. Electron microscopy showed the presence of autophagic vacuoles in cardiomyocytes. MDMA upregulated phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) at Thr172, mammalian target of rapamycin (mTOR) at Thr2446, Raptor at Ser792, and Unc51-like kinase (ULK1) at Ser555, suggesting activation of autophagy through the AMPK-mTOR pathway. The effects of autophagic inhibitors 3-methyladenine (3-MA) and chloroquine (CQ) on LC3-II levels indicated that MDMA enhanced autophagosome formation, but attenuated autophagosome clearance. MDMA also induced release of cathepsins into cytosol, and western blotting and electron microscopy showed cardiac troponin I (cTnI) degradation and myofibril damage, respectively. 3-MA, CQ, and a lysosomal inhibitor, E64c, inhibited cTnI proteolysis and improved contractile dysfunction after MDMA administration. In conclusion, MDMA causes lysosome destabilization following activation of the autophagy-lysosomal pathway, through which released lysosomal proteases damage myofibrils and induce LV systolic dysfunction in rat heart.

Inhibition of Autophagy Signaling via 3-methyladenine Rescued Nicotine-Mediated Cardiac Pathological Effects and Heart Dysfunctions

“…Our present findings that treatment with 3-MA significantly inhibited nicotine-mediated autophagy and eliminated the difference of I/R-induced cardiac injury and dysfunction between the saline control and nicotine-treated rats, suggest that nicotine-mediated heightened autophagy is one of the key molecular mechanisms contributing to ischemic heart injury and dysfunction. Consistent with our findings, a previous study has shown that enhanced autophagy leads to accumulation of autophagosomes and cardiac contractile dysfunction, and inhibition of autophagy with 3-MA treatment prevents heart injury [34]. In addition, other studies in rat primary cardiac myocytes in vitro have demonstrated that treatment of 3-MA or knockdown of Beclin 1 inhibits ischemia/ reperfusion-induced autophagy, leading to reduced cardiac injury and enhanced cardiac myocyte survival [35].…”

Binge Ethanol and MDMA Combination Exacerbates Toxic Cardiac Effects by Inducing Cellular Stress

“…Using phosphorylation state-specific antibody directed towards serine 31 phosphorylation of TH, present study showed that ethanol+MDMA exposure increased the levels of TH phosphorylated at serine 31 in the left ventricle concomitantly with the above described enhanced of NA turnover. Together this data provide evidence for TH phosphorylation after ethanol or MDMA exposure in the noradrenergic nerve terminals innervating the left ventricle and suggest an increased activity of cardiac sympathetic pathways which could be responsible of the cardiac toxicity induced by both drugs of abuse [ 39 – 43 ]. Furthermore, it has been proposed that drugs that perturb catecholaminergic function induce changes in THmRNA and protein expression [ 44 – 45 ].…”

A Metabolomics Study of Retrospective Forensic Data from Whole Blood Samples of Humans Exposed to 3,4-Methylenedioxymethamphetamine: A New Approach for Identifying Drug Metabolites and Changes in Metabolism Related to Drug Consumption

“…It could also be owed to decomposition of cyclic AMP. MDMA has been shown to initiate cyclic AMP activated phosphorylation of protein kinase A causing cardiac contractile dysfunctions and long-term potentiation in hippocampal synapses affecting cognitive functions in rat models. Urate is also a downstream metabolite of purine metabolism; however, this compound was predicted by LASSO logistic regression and found not to be significantly downregulated, thus a difference from controls is questionable.…”