Cardiac-Specific Knockout of ETA Receptor Mitigates Paraquat-Induced Cardiac Contractile Dysfunction

Abstract

Paraquat (1,1'-dim ethyl-4-4'-bipyridinium dichloride), a highly toxic quaternary ammonium herbicide widely used in agriculture, exerts potent toxic prooxidant effects resulting in multi-organ failure including the lung and heart although the underlying mechanism remains elusive. Recent evidence suggests possible involvement of endothelin system in paraquat-induced acute lung injury. This study was designed to examine the role of endothelin receptor A (ETA) in paraquat-induced cardiac contractile and mitochondrial injury. Wild-type (WT) and cardiac-specific ETA receptor knockout mice were challenged to paraquat (45 mg/kg, i.p.) for 48 h prior to the assessment of echocardiographic, cardiomyocyte contractile and intracellular Ca(2+) properties, as well as apoptosis and mitochondrial damage. Levels of the mitochondrial proteinsfor biogenesis and oxidative phosphorylation including UCP2, HSP90 and PGC1α were evaluated. Our results revealed that paraquat elicited cardiac enlargement, mechanical anomalies including compromised echocardiographic parameters (elevated left ventricular end-systolic and end-diastolic diameters as well as reduced factional shortening), suppressed cardiomyocyte contractile function, intracellular Ca(2+) handling, overt apoptosis and mitochondrial damage. ETA receptor knockout itself failed to affect myocardial function, apoptosis, mitochondrial integrity and mitochondrial protein expression. However, ETA receptor knockout ablated or significantly attenuated paraquat-induced cardiac contractile and intracellular Ca(2+) defect, apoptosis and mitochondrial damage. Taken together, these findings revealed that endothelin system in particular the ETA receptor may be involved in paraquat-induced toxic myocardial contractile anomalies possibly related to apoptosis and mitochondrial damage.

Proteomic signatures of acute oxidative stress response to paraquat in the mouse heart

“…To evaluate the proteomic responses to elevated oxidative stress, we first administered various doses of paraquat to C57BL/6J mice for 24 h. The animals (n = 4 per group) were exposed to three doses of paraquat (low—10 mg/kg; moderate—50 mg/kg; and high—75 mg/kg). The doses were chosen from a range previously reported for cardiac research models in the literature, with reports showing that exposure at 40–80 mg/kg for up to 48 hours induced acute oxidative stress responses as well as reduced contractile function and calcium handling in the mouse heart 15 , 18 , 21 – 23 . We first compared whether the applied paraquat doses elevated protein abundance of previously documented paraquat induced genes in the heart using mass spectrometry (Fig.…”

“…In humans, chronic environmental exposure to residues of paraquat used as pesticide has been linked to the development of Parkinson′s disease 12 , whereas in rare cases acute paraquat poisoning at higher dose has also been reported that leads to significant multi-organ toxicity and mortality 13 , 14 . In laboratory experiments, high doses of paraquat ( 20–80 mg/kg) have been broadly used as in rodents to reliably induce acute oxidative stress in the heart 15 – 18 and in the lung 19 , 20 . In this study, we compared normal and acute paraquat-stressed mouse hearts using quantitative mass spectrometry, with the goal of assessing the effect of acute oxidative damage on the cardiac proteome.…”

Proteomic signatures of acute oxidative stress response to paraquat in the mouse heart

“…The animals (n=4 per group) were exposed to three doses of paraquat (low -10 mg/kg; moderate -50 mg/kg; and high -75 mg/kg). The doses were chosen from a range previously reported for cardiac research models in the literature, with reports showing that exposure at 40-80 mg/kg for up to 48 hours induced acute oxidative stress responses as well as reduced contractile function and calcium handling in the mouse heart [13,[15][16][17][18]. We first compared whether the applied paraquat doses elevated protein abundance of previously documented paraquat induced genes in the heart using mass spectrometry (Figure 1a).…”

Toll‐like receptor 4 ablation rescues against paraquat‐triggered myocardial dysfunction: Role of ER stress and apoptosis

“…All mice were housed under well‐controlled conditions of temperature (22 ± 2°C), humidity (55 ± 5%) and a 12 h/12 h light‐dark cycle with access to food and water ad libitum . Four‐month‐old adult male TLR4 −/− and their age‐matched WT mice were delivered a single intraperitoneal injection of paraquat (45mg/kg, ∼100 μL, paraquat dichloride, Sigma‐Aldrich, St. Louis, MO) or the vehicle saline, and were examined 48 h later (Ge et al, ; Wang et al, ).…”

“…The paraquat chemical shares close structural similarity with the dopaminergic neurotoxin 1-methyl-4-phenyl-pyridine to prompt the onset of Parkinson's disease (McCormack et al, 2002;de Oliveira et al, 2015). In addition, paraquat exposure may also result in detrimental sequelae in the heart and lung (Chan et al, 2007;Wang et al, 2014;Qian et al, 2015;Wang et al, 2016;Xu et al, 2015;Qiaoli et al, 2016). In particular, paraquat impairs myocardial contractile function and survival (Chan et al, 2007;Ge et al, 2010;Wang et al, 2014).…”