Abstract
BackgroundCardiovascular disease is the leading cause of death among diabetic patients. Importantly, recent data highlight the apparent sexual dimorphism in the pathogenesis of cardiovascular disease in diabetics with respect to both frequency- and age-related risk factors. The disposition to cardiovascular disease among diabetic patients has been attributed, at least in part, to excess lipid supply to the heart culminating in lipotoxicity of the heart and downstream derangements. A confounding factor in obese animal models of diabetes is that increased peripheral lipid availability to the heart can induce cardio-metabolic remodeling independent of the underlying pathophysiology of diabetes, thus masking the diabetic phenotype. To that end, we hypothesized that the use of non-obese diabetic (NOD) animal models will reveal metabolic signatures of diabetes in a sex-specific manner.MethodsTo test this hypothesis, male and female NOD Goto-Kakizaki (GK) rats were used to assess the expression profile of 84 genes involved in lipid metabolism. In parallel, targeted lipidomics analysis was performed to characterize sex differences in homeostasis of non-esterified fatty acids (NEFA), acylcarnitines (AC), and triglycerides (TG).ResultsOur analysis revealed significant sex differences in the expression of a broad range of genes involved in transport, activation, and utilization of lipids. Furthermore, NOD male rats exhibited enhanced oxidative metabolism and accumulation of TG, whereas female NOD rats exhibited reduced TG content coupled with accumulation of AC species. Multi-dimensional statistical analysis identified saturated AC16:0, AC18:0, and AC20:0 as dominant metabolites in mediating sex differences in AC metabolism. Confocal microscopy of rat cardiomyocytes exposed to AC14:0, AC16:0, and AC18:0 confirmed induction of ROS with AC18:0 being more potent followed by AC14:0.ConclusionOverall, we demonstrate sex differences in myocardial AC and TG metabolism with implications for therapy and diagnosis of diabetic cardiovascular disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s13293-016-0077-7) contains supplementary material, which is available to authorized users.
Highlights
Cardiovascular disease is the leading cause of death among diabetic patients
Sex differences in expression profile of genes involved in lipid metabolism Figure 1a summarizes the ANOVA results for the differential expression of genes categorized by their metabolic functionality
Further studies are required to fully characterize the specificity and selectivity of ACs in inducing cardiac reactive oxygen species (ROS), insulin resistance, and downstream derangements in cardiomyocyte health and function in a sex-specific manner. In summary, these observations represent the first such report of sex differences in AC and TG metabolism as a potential metabolic signature of diabetes, which may contribute to downstream derangements in cardiac function in a sex-specific manner
Summary
Cardiovascular disease is the leading cause of death among diabetic patients. Importantly, recent data highlight the apparent sexual dimorphism in the pathogenesis of cardiovascular disease in diabetics with respect to both frequency- and age-related risk factors. While diabetes increases the risk of cardiovascular disease in both males and females, recent data suggests that heart disease is fivefold more common in diabetic women compared with twofold in men [4]. In the setting of myocardial infarction, diabetic women have a greater progression to heart failure and poorer outcome compared with diabetic males [5]. This “sexual dimorphism” is in contrast to the established notion of a “female advantage” in that premenopausal women in general are better protected from most common forms of cardiovascular disease compared to men [4, 6,7,8,9]. Excess lipid supply beyond the oxidative capacity of the heart results in accumulation of triglycerides (TG) and lipid intermediates, leading to lipotoxicity of the heart and downstream derangements, including generation of reactive oxygen species (ROS), inflammation, and cell death [15,16,17,18,19,20]
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