The Protection And Mechanism Of Low Dose Radiation Against Doxorubicin-induced Mitochondrial Damage In Cardiomyocytes Of Mice

Background and purpose:Doxorubicin(DOX), an anthraquinones antineoplastic agent, is widely used in many malignant tumors treatment because of its strong broad-spectrum antitumor effect. But it was greatly limited due to its serious toxicity of myocardium. So more and more clinicians have been being interested in the cardiotoxicity of DOX.The hormesis and adaptive effect induced by Low dose radiation(LDR) on normal tissues and organs(lung, kidney, bone, nerve, muscle, etc.), showed a protective effect against subsequent radiochemotherapy-induced damage. But few reports were found about LDR-induced protecetive activity to cardiac muscle tissues. We found that LDR may alleviates doxorubicin-induced cardiotoxicity in mice via suppression of oxidative stress and Mitochondrial-dependent apoptosis pathway in our previous study. In order to exploring the molecular mechanism of the protective effects of LDR on myocardial damage induced by DOX, we observed the mitochondrial morphology and detected the transcriptions and expressions of mitochondrial genes. We believe that our study will provide theoretical and experimental evidence in the anti-tumor treatment.Materials and methods:Eight weeks ages male Balb/c mice were randomly divided into 4 groups: Control group(0m Gy), DOX group, LDR group(75m Gy) and LDR-72h-DOX group(with intraperitoneal injection of DOX after 72 h LDR). Electron microscope was employed to observe the morphological characteristics of mitochondria. Whole genome microarray and q PCR were used to study the expression of all genes and mitochondrial genes in cardiomyocytes. Western blot analysis was used to detect proteins related to mitochondrial complexes. Activities of mitochondrial complexes as well as ATP levels in mitochondria were detected by some kits.Result:Electron micrographs showed that myofibrillar disordered and mitochondrial ridges decreased in DOX group mice and those changes in LDR-72-DOX group alleviated compared with DOX group.Whole genome microarray showed that DOX could induce genes differential expression of cardiomyocytes. The most significant involved in these differentially expressed genes were mitochondrial-related genes.QPCR showed that transcriptions of some mitochondrial genes(Atp P6v0d2、Co X8c) downregulated in DOX group. Transcriptions of some more mitochondrial genes(Atp6v0d2、Co X8c、Atp4a、Atp6v1c2,etc)upregulated in LDR-72-DOX group.The Western Blot indicated that expressions of some proteins related to mitochondrial complexes downregulated in DOX group and those proteins expressions upregulated with LDR pretreatment.Activities of mitochondrial complexes and ATP levels decreased in DOX group and which increased in LDR-72-DOX group compared with DOX group.Conclusion: In conclusion, LDR can induce pre-adaptation against the mitochondrial damage induced by DOX in cardiomyocytes. This pre-adaptation might improve the mitochondrial function through affecting expressions of some mitochondrial genes and proteins, increasing the activities of mitochondrial complexes and ATP levels in mitochondria. LDR is expected to be an assistsnt treatment in cardioprotection applied to antitumor therapy with DOX.