Abstract
BackgroundMetabolic syndrome (coexisting visceral obesity, dyslipidemia, hyperglycemia, and hypertension) is a prominent risk factor for cardiovascular morbidity and mortality, however, its effect on cardiac gene expression pattern is unclear. Therefore, we examined the possible alterations in cardiac gene expression pattern in male Zucker Diabetic Fatty (ZDF) rats, a model of metabolic syndrome.MethodsFasting blood glucose, serum insulin, cholesterol and triglyceride levels were measured at 6, 16, and 25 wk of age in male ZDF and lean control rats. Oral glucose tolerance test was performed at 16 and 25 wk of age. At week 25, total RNA was isolated from the myocardium and assayed by rat oligonucleotide microarray for 14921 genes. Expression of selected genes was confirmed by qRT-PCR.ResultsFasting blood glucose, serum insulin, cholesterol and triglyceride levels were significantly increased, glucose tolerance and insulin sensitivity were impaired in ZDF rats compared to leans. In hearts of ZDF rats, 36 genes showed significant up-regulation and 49 genes showed down-regulation as compared to lean controls. Genes with significantly altered expression in the heart due to metabolic syndrome includes functional clusters of metabolism (e.g. 3-hydroxy-3-methylglutaryl-Coenzyme A synthase 2; argininosuccinate synthetase; 2-amino-3-ketobutyrate-coenzyme A ligase), structural proteins (e.g. myosin IXA; aggrecan1), signal transduction (e.g. activating transcription factor 3; phospholipase A2; insulin responsive sequence DNA binding protein-1) stress response (e.g. heat shock 70kD protein 1A; heat shock protein 60; glutathione S-transferase Yc2 subunit), ion channels and receptors (e.g. ATPase, (Na+)/K+ transporting, beta 4 polypeptide; ATPase, H+/K+ transporting, nongastric, alpha polypeptide). Moreover some other genes with no definite functional clusters were also changed such as e.g. S100 calcium binding protein A3; ubiquitin carboxy-terminal hydrolase L1; interleukin 18. Gene ontology analysis revealed several significantly enriched functional inter-relationships between genes influenced by metabolic syndrome.ConclusionsMetabolic syndrome significantly alters cardiac gene expression profile which may be involved in development of cardiac pathologies in the presence of metabolic syndrome.
Highlights
It is well established that metabolic syndrome is a major risk factor for cardiovascular diseases [1,2,3,4]
Characterization of metabolic syndrome In order to verify the development of metabolic syndrome in male Zucker Diabetic Fatty (ZDF) rats, concentrations of several plasma metabolites and body weight were measured at week 6, 16 and 25 (Figure 1)
Serum insulin levels were significantly increased in ZDF rats compared to lean ones during the 25 weeks showing the presence of hyperinsulinemia in ZDF animals (Figure 1C)
Summary
It is well established that metabolic syndrome is a major risk factor for cardiovascular diseases [1,2,3,4]. Metabolic syndrome is defined as the coexistence of visceral obesity, dyslipidemia, hyperglycemia, and hypertension [5,6]. The effect of metabolic syndrome on gene expression pattern in various tissue types has been investigated in a few studies. In insulin sensitive tissues (liver, skeletal muscle and adipose tissue) [26] and pancreatic β-cells [27] obtained from the wellknown metabolic syndrome model (Zucker Diabetic Fatty rat, ZDF), altered gene expression pattern were shown when compared to their controls. Metabolic syndrome (coexisting visceral obesity, dyslipidemia, hyperglycemia, and hypertension) is a prominent risk factor for cardiovascular morbidity and mortality, its effect on cardiac gene expression pattern is unclear. We examined the possible alterations in cardiac gene expression pattern in male Zucker Diabetic Fatty (ZDF) rats, a model of metabolic syndrome
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