Abstract Body (Do not enter title and authors here): Background
Owing to the significant advances in cancer therapies, the survival time of advanced-stage cancer patients was longer than before but more and more cancer patients experience cancer therapy relateded cardiac dysfunction (CTRCD). Mild CTRCD has been shown to possess quite an impact on the prognosis. However, how to treat mild CTRCD is still unknown.
Hypothesis and Aims
Recently, some cohort studies showed that sacubitril/valsartan may alleviate the deterioration of severe CTRCD. Thus, we conducted this study to test the therapeutic efficacy of sacubitril/valsartan in mild CTRCD and to illustrate the mechanisms.
Methods
We used human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) as an in vitro platform to investigate the effect of sacubitril/valsartan on doxorubicin-treated hiPSC-CMs. We intraperitoneally injected doxorubicin 10 mg/kg/week for 2 weeks into mice to induce mild CTRCD and we treated these mice with placebo, valsartan and sacubitril/valsartan for 3 weeks to evaluate the therapeutic effect. Transthoracic echocardiography and pressure-volume loop analysis were used to assess cardiac function.
Results
Compared to the placebo-treated and the valsartan-treated groups, the sacubitril/valsartan-treated mice had lower mortality rate (placebo vs. valsartan vs. sacubitril/valsartan: 45% vs. 40% vs. 16%, respectively) and better cardiac function (placebo vs. valsartan vs. sacubitril/valsartan: 50.1±3.6% vs. 57.9±4.9% vs. 67.5±1.3%, respectively, p < 0.001). Those hiPSC-CMs treated with doxorubicin followed by sacubitril/valsartan had fewer apoptotic cells and lower level of reactive oxygen species (ROS). We did RNA sequencing analysis, revealing the production of ROS may play a crucial role in endoplasmic reticulum stress in doxorubicin-induced cardiomyocyte damage. Via P450 26B1 catalyst, sacubitril/valsartan treatment inhibited inositol-requiring enzyme 1α (IRE1α) phosphorylation and caspase 3 activation, resulting in reducing hiPSC-CM apoptosis.
Conclusions
Sacubitril/valsartan treatment alleviated doxorubicin-induced mild CTRCD and improved cardiac function and prognosis. Sacubitril/valsartan treatment would reduce apoptosis by reducing ROS-induced endoplasmic reticulum stress via inhibiting IRE1α/caspase 3 pathway.