αE-catenin is a component of adherens junctions that link the cadherin-catenin complex to the actin cytoskeleton. The signaling function of this protein was recently revealed. In the present study, we investigated the role of αE-catenin in the pathogenesis of heart failure. We mated αE-catenin conditional knockout mice with αMHC-Cre mice and evaluated their mutant offspring. We found that αE-catenin knockout caused enlargement of the heart and atria, fibrosis, the upregulation of hypertrophic genes, and the dysregulation of fatty acid metabolism via the transcriptional activity of Yap and β-catenin. The activation of canonical Wnt and Yap decreased the activity of main regulators of energy metabolism (i.e., adenosine monophosphate-activated protein kinase and peroxisome proliferator-activated receptor α) and dysregulated hypertrophic pathway activity (i.e., phosphatidylinositide 3-kinase/Akt, cyclic adenosine monophosphate/protein kinase A, and MEK1/extracellular signal regulated kinase 1/2). The loss of αE-catenin also negatively affected cardio-hemodynamic function via the protein kinase A pathway. Overall, we found that the embryonic heart-specific ablation of αE-catenin leads to the development of heart failure with age and premature death in mice. Thus, αE-catenin appears to have a crucial signaling function in the postnatal heart, and the dysfunction of this gene causes heart failure through canonical Wnt and Yap activation.
Background. Anthracycline antibiotics are one of the most effective anti-cancer drugs, but their cardiotoxicity what limits its therapeutic use.
Objective. To analyze the efficiency of enterosorption in doxorubicin-induced cardiohemodynamics violation.
Methods. Subchronic doxorubicin toxicity was modeled by injecting the anthracycline antibiotic intraperitoneally at a dose of 5 mg/kg once a week for 4 weeks, in total 20 mg/kg. Male Wistar rats were randomly distributed into 3 groups: control; DOX-group and DOX + enterosorbent C2 rats (γ = 0.18 g/cm3, BET area 2162 m2/g). Cardiohemodynamics was studied by the Millar Instruments, heart morphometry – by Avtandilov’s method.
Results. Mortality rate in DOX-group was 25%. Ejection fraction and Stroke work indices were lower compared to the control group, preload adjusted maximal power decreased by 57.6%, minimum volume and end-systolic volume increased by 76,2 and 67.5% respectively. End-systolic stiffness of left ventricle (Emax) as well as arterial elastance (Ea) and end-systolic pressure had tended to decrease. Indices of left ventricle (LV) volume at systole increased: V@dPdtmax – by 73.3%, V@dPdtmin – by 81.9%. End-diastolic volume increased by 54.6%. As for the dPdtmin, and Tau constant we observed the slight tendency to its decline. Endocardial surface of LV increased by 42.7%, Planimetric Index – by 40.4% compared to the control group of rats.
In DOX+C2 group mortality rate was 18.75%. We observed the strong tendency to normalization of the main indices compared to the DOX group and shrinking of the LV. We want to underline the positive trends especially in Ejection Fraction (from 39.62±10.50% to 46.23±11.46%) and Stroke Work (from 6406.50±3345.83 to 10363.14±7329.55 mmHg×uL) as important indicators of the effectiveness of cardiac pump function.
Conclusions. Enterosorption demonstrated positive impact on the doxorubicin-induced violated cardiohemodynamics and decreased the mortality rate. It is a ground for further investigations.
The original version of this article unfortunately contained a mistake. The published paper presented an incorrect version of Table 1. The corrected Table is given here.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.