To explore the role of peroxisome proliferator-activated receptor ␣ (PPAR␣)-mediated derangements in myocardial metabolism in the pathogenesis of diabetic cardiomyopathy, insulinopenic mice with PPAR␣ deficiency (PPAR␣ ؊/؊ ) or cardiac-restricted overexpression [myosin heavy chain (MHC)-PPAR] were characterized. Whereas PPAR␣ ؊/؊ mice were protected from the development of diabetes-induced cardiac hypertrophy, the combination of diabetes and the MHC-PPAR genotype resulted in a more severe cardiomyopathic phenotype than either did alone. Cardiomyopathy in diabetic MHC-PPAR mice was accompanied by myocardial longchain triglyceride accumulation. The cardiomyopathic phenotype was exacerbated in MHC-PPAR mice fed a diet enriched in triglyceride containing long-chain fatty acid, an effect that was reversed by discontinuing the high-fat diet and absent in mice given a medium-chain triglyceride-enriched diet. Reactive oxygen intermediates were identified as candidate mediators of cardiomyopathic effects in MHC-PPAR mice. These results link dysregulation of the PPAR␣ gene regulatory pathway to cardiac dysfunction in the diabetic and provide a rationale for serum lipid-lowering strategies in the treatment of diabetic cardiomyopathy. Results of epidemiologic studies indicate that diabetic individuals are at an extraordinarily high risk for the development of cardiovascular disease. The prevalence of risk factors including hyperlipidemia and hypertension certainly contribute to the high incidence of cardiovascular disease in the diabetic population. However, myocardial dysfunction (diabetic cardiomyopathy) is common in diabetic individuals independent of hypertension and coronary artery disease (1). In addition, morbidity and mortality after myocardial infarction is significantly greater in diabetic compared with nondiabetic patients (2). Although the pathogenesis of diabetic cardiomyopathy is poorly understood, recent evidence implicates perturbations in cardiac energy metabolism. Whereas mitochondrial fatty acid oxidation (FAO) is the chief energy source for the normal postnatal mammalian heart, the relative contribution of glucose utilization pathways is significant, allowing the plasticity necessary for steady ATP production in the context of diverse physiologic and dietary conditions (3). Because of the importance of insulin in the regulation of myocardial metabolism, chronic insulin deficiency or resistance results in a marked reduction in cardiac glucose utilization such that the heart relies almost exclusively on fatty acids to generate energy (4, 5). High rates of fatty acid utilization in the diabetic heart could lead to functional derangements related to accumulation of lipid intermediates, mitochondrial or peroxisomal generation of reactive oxygen species, or excessive oxygen consumption.Recently, we found that the diabetes-induced shift in cardiac fuel preference is associated with activation of the peroxisome proliferator-activated receptor (PPAR) ␣ gene regulatory system (6). PPAR␣ is a nuclear receptor that ...
Abstract-Previous studies have demonstrated a role for voltage-gated K ϩ (Kv) channel ␣ subunits of the Kv4 subfamily in the generation of rapidly inactivating/recovering cardiac transient outward K ϩ current, I to,f , channels. Biochemical studies suggest that mouse ventricular I to,f channels reflect the heteromeric assembly of Kv4.2 and Kv4.3 with the accessory subunits, KChIP2 and Kv1, and that Kv4.2 is the primary determinant of regional differences in (mouse ventricular) I to,f densities. Interestingly, the phenotypic consequences of manipulating I to,f expression in different mouse models are distinct. In the experiments here, the effects of the targeted deletion of Kv4. 1 Considerable progress has been made in characterizing the properties of myocardial Kv channels and in defining the roles of individual Kv channel pore-forming (␣) and accessory () subunits in the generation of these channels. 1 In adult mouse ventricles, for example, multiple Kv currents are coexpressed. 2-10 All available evidence suggests that ␣ subunits of the Kv4 subfamily underlie fast inactivating and recovering cardiac transient outward, I to,f , channels. 1 Biochemical studies suggest that mouse ventricular I to,f channels reflect the heteromeric assembly of Kv4.2 and Kv4.3. 10 In large mammals, however, Kv4.2 is not expressed, and I to,f channels are thought to reflect Kv4.3 homotetramers. 11,12 Multiple splice variants of Kv4.3 have been identified, 12 although the role(s) of these variants in the generation of I to,f channels is unclear.The accessory subunit, KChIP2, 13 coimmunoprecipitates with Kv4.2 and Kv4.3 from adult mouse ventricles, 10 and it has been reported that I to,f is eliminated in ventricular myocytes isolated from mice in which the KChIP2 locus was disrupted. 14 In canine ventricles, KChIP2 message 15,16 and protein 17 expression parallel variations in I to,f densities, suggesting that KChIP2 is the primary determinant of I to,f gradients. 15,17 In rodent ventricles, however, KChIP2 is uniformly expressed, and regional differences in I to,f densities are correlated with heterogeneities in Kv4.2 expression. 10,18 Interestingly, the phenotypic consequences of manipulating I to,f expression in vivo are distinct. 4,7,14,19 Recordings from ventricular myocytes isolated from transgenic mice expressing a pore mutant of Kv4.2, Kv4.2W362F, that functions as a dominant negative (Kv4.2DN), for example, revealed that I to,f is eliminated. 4 Materials and MethodsAnimals were handled in accordance with the NIH Guide for the Care and Use of Laboratory Animals; all protocols were approved by the Washington University Animal Studies Committee. The generation of the Kv4.2 Ϫ/Ϫ mice and the methods/protocols used in the present study are detailed in the online data supplement available at http://circres.ahajournals.org. Results Targeted Disruption of the KCND2 (Kv4.2) LocusIn the targeting construct used to generate Kv4.2 Ϫ/Ϫ mice ( Figure 1A), described in the expanded Materials and Methods section in the online data supp...
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