Inhibition of CACNA1H attenuates doxorubicin-induced acute cardiotoxicity by affecting endoplasmic reticulum stress.

Abstract Background Doxorubicin (DOX) is an anticancer drug that has been widely used in the clinic. However, recently its application has been limited due to the cardiotoxic effects it has caused. Severe cardiotoxicity of DOX causes cardiac hypertrophy that may lead to heart failure. It has previously been demonstrated that CACNA1H is re-expressed in hypertrophic cardiomyocytes. In this study, we aimed to investigate the role of CACNA1H in DOX-induced acute cardiotoxicity, and to investigate its possible underlying mechanisms of action involved. Methods Firstly, DOX-induced cardiac injury and changes in the expression of CACNA1H were evaluated. We explored the role of endoplasmic reticulum (ER) stress and apoptosis in mice that underwent DOX-induced cardiac injury. Next, to explore the role of CACNA1H in this process, we evaluated the changes in DOX-induced cardiac injury and ER stress after treatment with the CACNA1H specific inhibitor ABT-639. Next, we used ER stress inhibitor UR906 to verify the role of ER stress in DOX induced cardiotoxicity in H9C2 cells. Results DOX-treatment caused acute heart injury, leading to a decrease in cardiac function in mice, an increase in apoptosis of cardiac myocytes, and a significant increase in the expression level of CACNA1H in heart tissue. Next, mice were treated with CACNA1H inhibitor ABT-639 and we demonstrated that it partly protects myocardial function and reduces myocardial cell apoptosis. In addition, our data indicated that CACNA1H may play a role in alleviating DOX-induced cardiotoxicity by reducing the severity of ER stress because the use of ABT-639 significantly changed ER stress-related proteins, including p-PERK, PERK, CHOP, GRP78, ATF6, and ATF4. Furthermore, we found that the use of ER stress inhibitor UR906 in H9C2 cells significantly alleviated the increased expression of ER stress related proteins and apoptosis related proteins caused by DOX, and meanwhile reduced the degree of intracellular oxidative stress and intracellular calcium ion concentration. Conclusion CACNA1H inhibitors significantly alleviated DOX-induced cardiotoxicity and apoptosis induced by ER stress.