Abstract 16089: Activation of PPARα During the Progressive Phase of Heart Failure Improved Myocardial Energetics and Function in Pressure Overload Heart Failure
Background: Advanced failing heart loses its metabolic flexibility and relies more on glucose oxidation than fatty acid oxidation (FAO) as its preferential metabolism. Peroxisome proliferator-activated receptorα (PPARα) is known as a key regulator of this substrate shift. Recent studies have reported that neither cardiac specific PPARα transgenic mice nor PPARα deficient mice could protect against heart failure.
Method and Results: To investigate the role of PPARα on cardiac metabolism , we used transverse aortic constriction (TAC)-induced heart failure model. After eight weeks of TAC, left ventricular (LV) function was decreased with the reduction of PPARα expression. Administration of WY14643 (specific PPARα agonist) for eight weeks after TAC operation could not decrease the development of heart failure. Next, we examined the effect of WY14643 for late four weeks (from the forth to the eighth week), which were the progressive phase of heart failure. TAC-operated mice were randomly allocated into two groups : a HF group of untreated mice with heart failure, and a WY-HF group of mice with heart failure receiving WY14643. Eight weeks after TAC operation, LV contraction was preserved significantly in the WY-HF group with remarkable reduction in fibrosis compared to HF-group. The levels of PPARα downstream genes involved in fatty acid metabolism were significantly increased in the WY-HF group in comparison with the HF group, and the level of BNP expression was significantly reduced in the WY-HF group. Myocardial high energy phosphates were significantly preserved in the WY-HF group.
Conclusions: Present study suggested that activation of PPARα during the progressive phase of heart failure improved myocardial energetics and function in pressure-overloaded heart failure. Activation PPARα and upregulation of FAO will be a new therapeutic strategy for heart failure.
Author Disclosures: S. Kaimoto: None. A. Hoshino: None. M. Ariyoshi: None. Y. Okawa: None. M. Uchihashi: None. K. Fukai: None. K. Ono: None. S. Tateishi: None. E. Iwai-Kanai: None. S. Matoba: None.
- © 2014 by American Heart Association, Inc.