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

Abstract Background High prevalence of heart failure during and following cancer treatments remains a subject of intense research and therapeutic interest. Objectives This study investigated how different concentrations of doxorubicin (DOX) can affect the function of the cardiac cells. This study also examined whether activation of prokineticin receptor-1 (PKR1) by a nonpeptide agonist, IS20, prevents DOX-induced cardiovascular toxicity in mouse models. Methods We used cultured cardiomyocytes, endothelial cells (ECs), and epicardium-derived progenitor cells (EPDCs) for in vitro, assays and tumor-bearing and acute and chronic toxicity mouse models for in vivo assays. Results Brief exposure to cardiomyocytes with high-dose DOX increases the accumulation of reactive oxygen species (ROS) by inhibiting a detoxification mechanism via stabilization of cytoplasmic NRF2. Prolonged exposure to medium-dose DOX induces apoptosis in cardiomyocytes, ECs, and EPDCs. However, low-dose DOX promotes functional defects without inducing apoptosis in EPDCs and ECs. IS20 alleviates detrimental effects of DOX in cardiac cells via activating 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 normalizes an elevated serum marker of cardiotoxicity and vascular and EPDC deficits, attenuates apoptosis and fibrosis, and improves the survival rate and cardiac function. IS20 does not interfere with the cytotoxicity or antitumor effects of DOX in breast cancer lines or in a mouse model of breast cancer but attenuates the decreases in LV diastolic volume induced by acute DOX treatment. Conclusions This study identifies the molecular and cellular signature of dose-dependent DOX-mediated cardiotoxicity and provides evidence that PKR1 is a promising target to combat cardiotoxicity of cancer treatments

Pressure Overload–Mediated Sustained PKR2 (Prokineticin-2 Receptor) Signaling in Cardiomyocytes Contributes to Cardiac Hypertrophy and Endotheliopathies

International audienceChronic cardiac pressure overload, caused by conditions, such as hypertension, induces pathological hypertrophic growth of myocardium and vascular rarefaction, with largely unknown mechanisms. Here, we described that expression of the PKR2 (prokineticin-2 receptor) is increased in the cardiomyocytes of mice following transaortic constriction pressure overload–mediated pathological hypertrophy. To identify PKR2-induced pathways, we performed microarray analysis on TG-PKR2 (transgenic mice overexpressing cardiomyocyte-restricted human PKR2) hearts and cytokine analyses in hPKR2 overexpressing H9c2-lines (PKR2-cardiomyocytes). An enrichment of activin pathway gene sets was found in both TG-PKR2 and transaortic constriction-operated hearts. Elevated levels of 2 cytokines activin A and its coreceptor, sENG (soluble Endoglin), were found in both PKR2-cardiomyocytes and in PKR2-cardiomyocytes conditioned medium. ELISA analyses of the cardiomyocytes derived from both TG-PKR2 and transaortic constriction hearts revealed high levels of these cardiokines that were repressed with antibodies blocking PKR2, indicating a PKR2-dependent event. The conditioned medium of PKR2-cardiomyocytes induced fenestration of endothelial cells and inhibited tube-like formations. These endotheliopathies were blocked by either depleting activin A or sENG from conditioned medium or by using 2 pharmacological inhibitors, follistatin, and TRC105. In addition, similar endotheliopathies were produced by exogenous administration of activin A and ENG. Prolonged exposure to prokineticin-2 in PKR2-cardiomyocytes increased cell volume by the PKR2/Gα 12/13 /ERK5-pathway. Activation of the PKR2/Gα 12/13 /matrix metalloprotease-pathway promoted both activin A and sENG release. This study reveals that pressure overload–mediated PKR2 signaling in cardiomyocytes contributes to cardiac hypertrophy through autocrine signaling, and vascular rarefaction via cardiac cytokine-mediated cardiomyocyte–endothelial cell communications. Our results may contribute to the development of potential therapeutic targets for heart failure