Myocardial infarction in rats causes partial impairment in insulin response associated with reduced fatty acid oxidation and mitochondrial gene expression

Abstract

Objective: Myocardial infarction leads to contractile dysfunction. In patients with diabetes, impaired contractility has been associated with the loss of insulin effects and mitochondrial dysfunction. We assessed cardiac insulin sensitivity and mitochondrial and contractile function in rats after ligation of the left coronary artery. Methods: At 2 weeks after left coronary artery ligation, we performed echocardiography in vivo and assessed the substrate use and insulin response in the isolated working heart and the regulation of insulin (Akt, glucose transporter type 4) and mitochondrial signaling (p38 mitogen-activated protein kinase, peroxisome proliferatoractivated receptor-g coactivator 1a, mitochondrial transcription factor A) using polymerase chain reaction and Western blotting. Results: The infarcted hearts were dilated and had a reduced ejection fraction (ejection fraction < 50%). The basal glucose oxidation was preserved, but the fatty acid oxidation was significantly reduced. Insulin's effect on substrate oxidation was significantly impaired for both the decrease in fatty acid oxidation and the increase in glucose oxidation. However, insulin-stimulated glucose uptake was normal in the infarcted hearts, consistent with normal insulin-induced phosphorylation of Akt and unchanged mRNA expression of glucose transporter type 4. The impaired oxidative response to insulin was associated with reduced mRNA expression of the genes regulating fatty acid oxidation (long-chain-acyl-coenzyme A dehydrogenase, carnitine palmitoyltransferase 1, peroxisome proliferator-activated receptor-a) and mitochondrial biogenesis (mitochondrial transcription factor A). Although mRNA expression of the mitochondrial master regulator peroxisome proliferator-activated receptor-g coactivator 1a was normal in the infarcted hearts, the protein expression of its post-transcriptional activator, p38 mitogen-activated protein kinase, was significantly reduced. Conclusions: Myocardial infarction in rats caused partial insulin resistance at the level of substrate oxidation, which was associated with mitochondrial and cardiac contractile dysfunction. Mitochondrial dysfunction was characterized by a reduced capacity to oxidize fatty acids and might have resulted from impaired mitochondrial biogenesis through the lack of p38 mitogen-activated protein kinase.

Cardiac Metabolism in Heart Failure

“…In the presence of systolic dysfunction, cardiac glucose uptake was found to be decreased following aortic constriction in mice 57 but unchanged in rats with myocardial infarction, 58 and increased in Dahl salt-sensitive rats. 48 In compensated hypertrophy, induced by abdominal aortic constriction, glycolysis was modestly increased without changes in glucose oxidation.…”

A Review of the Molecular Mechanisms Underlying the Development and Progression of Cardiac Remodeling

“…Similarly, PGC-1 β was shown to be responsible for mitochondrial dysfunction resulting from accelerated myocardial hypertrophy following pressure overload [126]. Furthermore, expression of p38-MAPK was found to be reduced after MI, leading to an impaired capability to oxidize fatty acids, which in turn contributes to LV dilatation [127]. Interestingly, in vivo overexpression of TFAM in a mouse model of MI improved mt-DNA copy number and mitochondrial complex activity, while reducing myocyte hypertrophy, interstitial fibrosis, apoptosis, and chamber dilatation, thus slowing down the overall progression of LV remodeling [128].…”

Mitochondrial dysfunction and its impact on diabetic heart

“…In contrast, the data on cardiac glucose use are less consistent [43–45]. In the presence of systolic dysfunction, cardiac glucose uptake was decreased in mice after aortic constriction [43], while unchanged in rats with myocardial infarction [46], and increased in Dahl salt-sensitive rats [39]. The impaired glucose oxidation that parallels systolic dysfunction might be attributable in part to mitochondrial dysfunction, reduced expression of genes involved in glycolysis and glucose oxidation, or decreased abundance of the PDH complex [39, 47].…”

“…The impaired glucose oxidation that parallels systolic dysfunction might be attributable in part to mitochondrial dysfunction, reduced expression of genes involved in glycolysis and glucose oxidation, or decreased abundance of the PDH complex [39, 47]. Osorio et al showed increased glucose oxidation rates in failing dog hearts induced by rapid pacing [46], and Dávila-Román et al demonstrated higher total rates of glucose use in patients with idiopathic dilated cardiomyopathy [48]. Thus the changes in glucose oxidation in cardiac myocytes may depend on both the stage and the pathogenesis of heart failure.…”