Protection against Doxorubicin-Induced Cardiotoxicity through Modulating iNOS/ARG 2 Balance by Electroacupuncture at PC6.

Jingya Wang,Shengxuan Sun,Guoqi Shi,Xiaoli Wu,Qi Guo,Jie Li,Lin Yao,R William Caldwell,Yongjun Chen,Ruth B Caldwell

doi:10.1155/2021/6628957

Abstract

Background Doxorubicin (DOX) is a commonly used chemotherapeutic drug but is limited in clinical applications by its cardiotoxicity. Neiguan acupoint (PC6) is a well-recognized acupoint for the treatment of cardiothoracic disease. However, whether acupuncture at PC6 could be effective in preventing DOX-induced cardiotoxicity is still unknown. Methods A set of experiments were performed with myocardial cells, wild type, inducible nitric oxide synthase knockout (iNOS-/-), and myocardial-specific ablation arginase 2 (Myh6-ARG 2-/-) mice. We investigated the protective effect and the underlying mechanisms for electroacupuncture (EA) against DOX-induced cardiotoxicity by echocardiography, immunostaining, biochemical analysis, and molecular biotechnology in vivo and in vitro analysis. Results We found that DOX-mediated nitric oxide (NO) production was positively correlated with the iNOS level but has a negative correlation with the arginase 2 (ARG 2) level in both myocardial cells and tissues. Meanwhile, EA at PC6 alleviated cardiac dysfunction and cardiac hypertrophy in DOX-treated mice. EA at PC6 blocked the upregulation of NO production in accompanied with the downregulated iNOS and upregulated ARG 2 levels in myocardial tissue induced by DOX. Furthermore, knockout iNOS prevented cardiotoxicity and EA treatment did not cause the further improvement of cardiac function in iNOS-/- mice treated by DOX. In contrast, deficiency of myocardial ARG 2 aggravated DOX-induced cardiotoxicity and reduced EA protective effect. Conclusion These results suggest that EA treatment at PC6 can prevent DOX-induced cardiotoxicity through modulating NO production by modulating the iNOS/ARG 2 balance in myocardial cells.

Highlights

Doxorubicin (DOX) is an anthracycline antibiotic that is widely used to treat leukemias, Hodgkin’s lymphoma, cancers of the bladder and breast, multiple myeloma, and other cancers [1, 2]
We found that nitric oxide (NO) levels in both serum and heart were markedly increased in the DOX-treated group compared to the control group and this increase was blocked in the EA treatment group, suggesting that EA at PC6 prevented the DOX-induced increases in NO production (Figures 3(a) and 3(b))
We found that EA at PC6 with 2 Hz effectively protected against DOX-induced cardiotoxicity and overactivated inducible nitric oxide synthase (iNOS)-NO signaling

Summary

Introduction

Doxorubicin (DOX) is an anthracycline antibiotic that is widely used to treat leukemias, Hodgkin’s lymphoma, cancers of the bladder and breast, multiple myeloma, and other cancers [1, 2]. We found that DOX-mediated nitric oxide (NO) production was positively correlated with the iNOS level but has a negative correlation with the arginase 2 (ARG 2) level in both myocardial cells and tissues. EA at PC6 blocked the upregulation of NO production in accompanied with the downregulated iNOS and upregulated ARG 2 levels in myocardial tissue induced by DOX. Knockout iNOS prevented cardiotoxicity and EA treatment did not cause the further improvement of cardiac function in iNOS-/- mice treated by DOX. Deficiency of myocardial ARG 2 aggravated DOX-induced cardiotoxicity and reduced EA protective effect. These results suggest that EA treatment at PC6 can prevent DOX-induced cardiotoxicity through modulating NO production by modulating the iNOS/ARG 2 balance in myocardial cells

Methods

Results

Discussion

Conclusion