Dual PPARα/γ ligand TZD18 improves myocardial metabolic remodeling after myocardial infarction in rats

To investigate the changes in myocardial energy metabolism and the effect of peroxisome proliferator-activated receptor alpha/gamma (PPARα/γ) dual agonist TZD18 on myocardial energy metabolism in rats with heart failure after myocardial infarction.

The myocardial infarction model was established by ligating the left anterior descending coronary artery. The rats were randomly divided into the myocardial infarction group (MI group), the TZD18 intervention group (TZD18 group), and the shame surgery group (sham group). 8 weeks later, the blood flow parameters were measured by carotid arterial cannulas, and ventricular remodeling indexes were calculated. Hearts were extracted from rats after the execution. The expressions of PPARα/γ mRNA and α/β-MHC mRNA were detected by reverse transcription-polymerase chain reaction (RT-PCR). The mitochondrial oxidative respiration activity was measured by a bio-tissue oxygen consumption meter, the content of adenosine in mitochondria was measured by high-performance liquid chromatography, and tritium-labeled adenosine diphosphate incorporation assay was used to detect the transport activity of adenosine nucleotide translocases (ANT).

The expression of PPARα/γ mRNA and the ratio of α/β-MHC mRNA in the MI group were significantly decreased, the content of high energy phosphates, respiration activity, ANT transport activity in mitochondria were significantly decreased, the hemodynamic indexes were disturbed and left ventricular weight/body weight ratio (LVW/BW) significantly became higher. TZD18 intervention could increase the expression level of PPARα/γ mRNA and up-regulate the ratio of α/β-MHC mRNA, thus improving mitochondrial respiratory activity and ANT transport activity in rats with heart failure after myocardial infarction, increasing the content of high energy phosphates in mitochondria and improving the remodeling indexes in the ventricle.

TZD18 increases both the expression of enzymes related to myocardial energy metabolism and the content of high-energy phosphates in mitochondria. Also, it improves the respiratory activity and ANT transport activity by activating PPARα/γ genes, thus improving the generation and delivery of myocardial energy and protecting the myocardial cells.