Role of Endothelium in Doxorubicin-Induced Cardiomyopathy

Abstract

SummaryThe clinical use of doxorubicin in cancer is limited by cardiotoxic effects that can lead to heart failure. Whereas earlier work focused on the direct impact of doxorubicin on cardiomyocytes, recent studies have turned to the endothelium, because doxorubicin-damaged endothelial cells can trigger the development and progression of cardiomyopathy by decreasing the release and activity of key endothelial factors and inducing endothelial cell death. Thus, the endothelium represents a novel target for improving the detection, management, and prevention of doxorubicin-induced cardiomyopathy.

Sinapic Acid Ameliorates Oxidative Stress, Inflammation, and Apoptosis in Acute Doxorubicin‐Induced Cardiotoxicity via the NF‐κB‐Mediated Pathway

“…Certainly, it has been established that elevated levels of inflammatory markers are associated with enhanced oxidative stress, which is known to initiate inflammatory reactions by activating NF-κB, which regulates the release of cytokines [44]. DOX treatment generates ROS, disrupts endotheliumbased cardiac myocyte functions, and encourages the release of endothelial cell-derived ET-1, PGI2, NO, and NRG-1, causing cardiac toxicity [45]. Generation of NO leads to peroxynitrite ions that induce nitrostative stress in the myocardium, suppress myocardial contractility, and induce apo-ptosis [46,47].…”

Association of Genetic Variants at TRPC6 With Chemotherapy-Related Heart Failure

“…Our TWAS experiment showed association of TRPC6 imputed gene expression in the left ventricle with a decline in LVEF, hence we began this experiment in human iPSC-derived cardiomyocytes. However, given that TRPC6 is more highly expressed in vascular tissue than in the heart ( 50 ), (an important consideration for functional validation) and doxorubicin cardiotoxicity may also be mediated through endothelial dysfunction ( 51 ), we also performed the experiment in human endothelial cells. Pre-treatment of both cell types with GsMTx-4 significantly reduced doxorubicin-induced apoptosis, suggesting that inhibition of TRPC6 may reduce cardiotoxicity in patients receiving doxorubicin.…”

Analysis of Doxorubicin and Doxorubicinol in Dried Blood Spot of Breast Cancer Patients for Monitoring the Cardiotoxicity of Doxorubicin

“…Other previous study by Covarrubias et al, (2009) stated that the higher concentration of doxorubicinol has a relationship with untranslated CBR1 polymorphism [12]. Based on study, it was stated that the incidence of cardiomyopathy increased at a rate of 4% at doses of 500-550 mg/m 2 , 18% at doses of 551-600 mg/m 2 and 36% at doses>600 mg/m 2 (all cumulative doses) [2]. In this study, the obtained cumulative doses of all patients were in the range of 49.11 mg/m 2 to 303.70 mg/m 2 based on doses that accepted by the patient according to the body surface area.…”

“…The use of doxorubicin in the long term causes the accumulation of doxorubicinol in the body, which can increase the risk of heart problems. Current evidence indicates that the incidence of cardiomyopathy at a rate of 4% at doses of 500-550 mg/m 2 , 18% at doses of 551-600 mg/m 2 and 36% at doses>600 mg/m 2 (all cumulative doses) [1,2].…”