Role of PPARα/PGC-1α in doxorubicin induced mouse dilated cardio-myopathy

AIM: To investigate the changes of peroxisome proliferator-activated receptors (PPAR)α/peroxisome proliferator activated receptor coactivator 1 alpha (PGC-1α) in doxorubicin (DOX) induced dilated cardiomyopathy (DCM) and its effect on the energy metabolism and myocardial function in mice. METHODS: Forty mice were randomly divided into 4 groups: control group, DOX group, PPARα inhibitor group and PPARα agonist group. The DCM model was established by injection of DOX. The protein levels of PPARα/PGC-1α were detected. The PPARα inhibitor and PPARα agonist were used 2 weeks beforeinjection of DOX. The contents of adenine acid and phosphocreatine (Pcr) in the mitochondria were measured by high-performance liquid chromatography (HPLC). The ANT activity was analyzed by the atractyloside-inhibitor stop technique. The changes of the echocardiography and hemodynamics were also observed. RESULTS: DOX induced DCM model was successfully established. The protein levels of PPARα and PGC-1α in control group were significantly higher than those in DOX group (P<0.05). Both of the high-energy phosphate contents and the transport activity of ANT were decreased in DOX group (P<0.05), and the hemodynamic parameters were disordered (P<0.01). Compared with DOX group, PPARα inhibitor pre-treatment significantly reduced the PPARα/PGC-1α expression. Meanwhile, high-energy phosphate contents in the mitochondria and the ANT transport activity of the mitochondria decreased, as well as the left ventricular function (P<0.05). On the other hand, PPARα agonist significantly increased the expression of PPARα and PGC-1α, and improved the transport activity of ANT. In addition, the hemodynamic parameters were ameliorated, but the high-energy phosphate contents of the mitochondria did not significantly change. CONCLUSION: PPARα/PGC-1α plays an important role in the regulation of ANT transport activity in dilated cardiomyopathy induced by DOX, and the activation of PPARα/PGC-1α has protective effects on the DCM induced by DOX.