Prokineticin Receptor-1 Signaling Inhibits Dose- and Time-Dependent Anthracycline-Induced Cardiovascular Toxicity Via Myocardial and Vascular Protection

Prokineticin Receptor-1 Signaling Inhibits Dose- and Time-Dependent Anthracycline-Induced Cardiovascular Toxicity Via Myocardial and Vascular Protection

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Objectives: This study investigated how different concentrations of doxorubicin (DOX) can affect the function of cardiac cells.This study also examined whether activation of prokineticin receptor (PKR)-1 by a nonpeptide agonist, IS20, prevents DOX-induced cardiovascular toxicity in mouse models.Background: High prevalence of heart failure during and following cancer treatments remains a subject of intense research and therapeutic interest.Methods: This study used cultured cardiomyocytes, endothelial cells (ECs), and epicardium-derived progenitor cells (EDPCs) for in vitro assays, tumor-bearing models, and acute and chronic toxicity mouse models for in vivo assays.

Results: Brief exposure to cardiomyocytes with high-dose DOX increased the accumulation of reactive oxygen species (ROS) by inhibiting MISC a detoxification mechanism via stabilization of cytoplasmic nuclear factor, erythroid 2.Prolonged exposure to medium-dose DOX induced apoptosis in cardiomyocytes, ECs, and EDPCs.However, low-dose DOX promoted functional defects without inducing apoptosis in EDPCs and ECs.IS20 alleviated detrimental effects of DOX in cardiac cells by activating the serin threonin protein kinase B (Akt) or mitogen-activated protein kinase pathways.

Genetic or pharmacological inactivation of PKR1 subdues these effects of IS20.In a chronic mouse model of DOX cardiotoxicity, IS20 normalized an elevated serum marker of cardiotoxicity and vascular and EDPC deficits, attenuated apoptosis and fibrosis, and improved Clothing - Womens Bottoms - Pants the survival rate and cardiac function.IS20 did not interfere with the cytotoxicity or antitumor effects of DOX in breast cancer lines or in a mouse model of breast cancer, but it did attenuate the decreases in left ventricular diastolic volume induced by acute DOX treatment.Conclusions: This study identified the molecular and cellular signature of dose-dependent, DOX-mediated cardiotoxicity and provided evidence that PKR-1 is a promising target to combat cardiotoxicity of cancer treatments.