Objective: This study aims to investigate the effects and their mechanisms of PPARα and PGC-1α pathways in doxorubicin induced dilated cardiomyopathy in mice.
Methods: The model of dilated cardiomyopathy (DCM) was established by injecting doxorubicin in mice. The 40 surviving mice were divided randomly into control group, doxorubicin model group, PPARα inhibitor and PPARα agonist group. The PPARα/PGC-1α proteins were detected. The size of adenine acid pool (ATP, ADP, AMP) and phosphocreatine (Pcr) in mitochondria were measured by HPLC. The ANT activity was detected by the atractyloside-inhibitor stop technique. The echocardiography and hemodynamic changes were detected in each group after PPARα inhibitor and PPARα agonist treatment for 2 weeks.
Results: The DOX induced DCM model were successfully established. The expression of PPARα and PGC-1α protein level in normal group were significantly higher than that in DOX model group (P<0.05). Both the high-energy phosphate content and the transport activity of ANT were decreased in DOX group (P<0.05), and the hemodynamic parameters were disorder (P<0.01). Compared with Dox group, PPARα inhibitor intervention significantly reduce the expression of PPARα/PGC-1α, high-energy phosphate content in the mitochondria had no significant change (P>0.05), but the ANT transport activity of mitochondria decreased significantly (P<0.05), the left ventricular function decreased. On the other side, PPARα agonist intervention significantly increased the expression of PPARα and PGC-1α, improved transport activity of ANT, the hemodynamic parameters was ameliorated (P<0.05), but the high-energy phosphate content of mitochondria did not change significantly (P>0.05).
Conclusion: There was lower expression of PPARα and PGC-1α in DOC induced DCM in mice. Promotion of PPARα can improve myocardia energy metabolism and delay the occurrence of heart failure.
Keywords: PGC-1α; PPARα; dilated cardiomyopathy; doxorubicin; energy metabolism.