Abstract
Doxorubicin (DOX) is an effective anticancer drug, but its therapeutic use is limited by its cardiotoxicity. The principal mechanisms of DOX-induced cardiotoxicity are oxidative stress and apoptosis in cardiomyocytes. Orosomucoid 1 (ORM1), an acute-phase protein, plays important roles in inflammation and ischemic stroke; however, the roles and mechanisms of ORM1 in DOX-induced cardiotoxicity remain unknown. Therefore, in the present study, we aimed to investigate the function of ORM1 in cardiomyocytes experiencing DOX-induced oxidative stress and apoptosis. A DOX-induced cardiotoxicity animal model was established in C57BL/6 mice by administering an intraperitoneal injection of DOX (20 mg/kg), and the control group was intraperitoneally injected with the same volume of sterilized saline. The effects were assessed after 7 d. Additionally, H9c2 cells were stimulated with DOX (10 μM) for 24 h. The results showed decreased ORM1 and increased oxidative stress and apoptosis after DOX stimulation in vivo and in vitro. ORM1 overexpression significantly reduced DOX-induced oxidative stress and apoptosis in H9c2 cells. ORM1 significantly increased the expression of nuclear factor-like 2 (Nrf2) and its downstream protein heme oxygenase 1 (HO-1) and reduced the expression of the lipid peroxidation end product 4-hydroxynonenal (4-HNE) and the level of cleaved caspase-3. In addition, Nrf2 silencing reversed the effects of ORM1 on DOX-induced oxidative stress and apoptosis in cardiomyocytes. In conclusion, ORM1 inhibited DOX-induced oxidative stress and apoptosis in cardiomyocytes by regulating the Nrf2/HO-1 pathway, which might provide a new treatment strategy for DOX-induced cardiotoxicity.
Highlights
Heart failure is a prevalent disease worldwide, representing a severe manifestation and end stage of most heart diseases
We aimed to investigate the potential relationship between Orosomucoid 1 (ORM1) and nuclear factor-like 2 (Nrf2) and clarify the roles of ORM1 in the oxidative stress and cell apoptosis resulting from DOX-induced cardiomyocyte toxicity
To determine the levels of myocardial injury caused by DOX, we tested the serum Lactate Dehydrogenase (LDH) and CKMB levels and found that the difference was statistically significant between the DOXtreated and control groups (Supplementary Figure 1b-c)
Summary
Heart failure is a prevalent disease worldwide, representing a severe manifestation and end stage of most heart diseases. Heart failure significantly decreases the quality of life of patients and causes a substantial economic burden on patient families and society but is associated with a high mortality rate. Heart failure is known as “the final battlefield of cardiovascular disease of the 21st century”. The incidence rate of cancer is more than one-third worldwide, and cardiovascular disease is the two causes of death in developed countries. DOX plays an important role in the treatment of many cancers, as 32% of patients with breast cancer, 57-70% of elderly patients with lymphoma, and 50-60% of children with cancer have been treated with anthracycline drugs [3,4,5,6]. DOX has been included in the World Health Organization (WHO) model list of essential medicines, as a milestone of cancer therapy development and one of the most commonly used antitumor anthracycline antibiotics
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