<b>Downregulation of Peroxisme Proliferator Activated Receptor Gamma Co-Activator 1&alpha; in Diabetic Rats</b>

Abstract

SUMMARYDiabetes mellitus (DM), which induces alterations in energy metabolism, is the leading cause of cardiovascular disease. We postulated that peroxisome proliferator activated receptor-γ coactivator 1α (PGC-α), a transcriptional coactivator that is the primary regulator of oxidative metabolism and mitochondrial biogenesis, and cardiac function are depressive in DM and simvastatin and losartan therapy can improve the affects of DM on mRNA expression of PGC-1α and cardiac function. An experimental model of DM (induced by streptozocin 60 mg/kg) in adult male rats (n = 24) was used to investigate the mRNA expression of PGC-1α in the left ventricular myocardium. These rats were divided into group I (insulin therapy only, n = 8), group II (insulin plus simvastatin 20 mg/kg/day orally, n = 8), and group III (insulin plus losartan 20 mg/kg/day orally, n = 8). Diabetic rats and 8 healthy rats (group IV) were sacrificed at 3 weeks following DM induction. The mRNA expression of PGC-1α was measured using real-time polymerase chain reaction (RT-PCR). Additionally, transthoracic echocardiography was performed on days 0 and 21. The experimental results indicated that the mRNA expression of PGC-1α and the left ventricular ejection fraction (LVEF %) were significantly lower in groups I, II and III than in group IV (all P < 0.001). However, the mRNA expression of PGC-1α and the LVEF were significantly higher in group III than in groups I and II (both P < 0.01). Conversely, mRNA expression of PGC-1α and LVEF did not differ between groups I and II (P > 0.5). In conclusion, DM induces suppression of mRNA expression of PGC-1α and LV function in diabetic rats. Losartan and not simvastatin therapy improved the LV function and the expression of this mitochondrial-biogenesis regulator. (Int Heart J 2006; 47: 901-910)

Impact of Hyperglycemic Control on Left Ventricular Myocardium A Molecular and Cellular Basic Study in a Diabetic Rat Model

“…Consistently, DM has been found to induce suppression of mRNA expression of PGC-1α and deterioration of LV function in diabetic rats. 30) Therefore, our findings and those from previous studies 22,30,32) may explain the suppression of LV function in poorly controlled hyperglycemic rats.…”

“…The procedure and protocol were described in detail in a previous recent report. 30) Procedure and protocol for measurement of reactive oxygen species (ROS): 2',7'-Dichlorodihydrofluorescin diacetate (H 2 DCFDA, Molecular Probes) was dissolved in DMSO at a concentration of 25 mg/mL. After being diluted with 50% ethanol to a final concentration of 2.5 mg/mL, 6 μg per gram of rat body weight was administered to the dorsal vein of the penis immediately following echocardiographic examination as modified from a method previously described.…”

Comparison of Losartan and Carvedilol on Attenuating Inflammatory and Oxidative Response and Preserving Energy Transcription Factors and Left Ventricular Function in Dilated Cardiomyopathy Rats

“…10) Interestingly, our recent studies have also shown that PGC-1α gene expression is significantly reduced in DM rats with LV dysfunction and in rats with acute myocardial infarction (AMI). 11,12) In the present study, one of the important findings was that PGC-1α gene expression was remarkably suppressed in DCM rats. Moreover, the cytochrome C level in mitochondria was also markedly decreased in the DCM rats.…”

“…Our findings, therefore, corroborate those of previous experimental studies. [10][11][12] Of interest in the present study is that losartan was comparable to carvedilol in preserving LV function and cytochrome C levels in mitochondria. Additionally, losartan was found to be superior to carvedilol in inhibiting PGC-1α gene down-regulation in induced DCM.…”

“…5,6,9) Experimental studies have established close relationships between depressed energy transcription factors and cardiac function disturbances such as left ventricular (LV) dysfunction in DCM, diabetic cardiomyopathy, and myocardial infarction. [10][11][12] Furthermore, changes in connexin43 (Cx43) expression patterns have been demonstrated to be associated with various cardiac pathologies and contribute to the initiation of cardiac arrhythmia. [13][14][15] The integrity of Cx43 in DCM, however, has not been thoroughly investigated.…”