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Gender Differences in Cardiac Remodeling Induced by a High-Fat Diet and Lifelong, Low-Dose Cadmium Exposure.

ABSTRACT: Childhood obesity, which is prevalent in developed countries, is a metabolic risk factor for cardiovascular disease. Cadmium (Cd), a ubiquitous environmental toxic metal, also has deleterious effects on the cardiovascular system. However, the combined effects of a high-fat diet (HFD) and lifelong, low-dose Cd exposure on cardiac remodeling remain unclear. This study aims to determine the effects of combined HFD and Cd exposure on cardiac remodeling, as well as gender-specific differences in the response. C57BL/6J mice were exposed to Cd at a low dose (L-Cd, 0.5 ppm) or high dose (H-Cd, 5 ppm) via drinking water from conception to sacrifice. After being weaned, the offspring mice were fed with a HFD (42% kcal from fat) for an additional 10 weeks. H-Cd exposure significantly increased Cd accumulation in the hearts of both parents and their offspring; a HFD showed no added effects on cardiac Cd content. H-Cd exposure increased cardiac metallothionein protein levels only in female mice, regardless of dietary intake. Histological analysis revealed that H-Cd exposure combined with a HFD induced cardiac hypertrophy and fibrosis only in female mice. This was further supported by elevated expression of ANP and COL1A1 protein levels along with COL1A1, COL1A2, and COL3A1 mRNA levels. Profibrotic markers PAI-1, CTGF, and FN were also elevated in HFD/H-Cd-exposed female mice. Levels of the oxidative stress marker 3-NT significantly increased in the hearts of HFD-fed female mice, whereas Cd exposure showed no additional effects. Of all the antioxidant markers examined, levels of CAT significantly increased in mice fed a HFD, regardless of gender and Cd exposure. In summary, a HFD combined with lifelong, low-dose Cd exposure induces cardiac hypertrophy and fibrosis in female but not male mice, a response that is independent of oxidative stress.

SUBMITTER: Liang Y

PROVIDER: S-EPMC7060501 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Project description:BackgroundTo study the pathogenesis of diabetic cardiomyopathy, reliable animal models of type 2 diabetes are required. Physiologically relevant rodent models are needed, which not only replicate the human pathology but also mimic the disease process. Here we characterised cardiac metabolic abnormalities, and investigated the optimal experimental approach for inducing disease, in a new model of type 2 diabetes.Methods and resultsMale Wistar rats were fed a high-fat diet for three weeks, with a single intraperitoneal injection of low dose streptozotocin (STZ) after fourteen days at 15, 20, 25 or 30 mg/kg body weight. Compared with chow-fed or high-fat diet fed control rats, a high-fat diet in combination with doses of 15-25 mg/kg STZ did not change insulin concentrations and rats maintained body weight. In contrast, 30 mg/kg STZ induced hypoinsulinaemia, hyperketonaemia and weight loss. There was a dose-dependent increase in blood glucose and plasma lipids with increasing concentrations of STZ. Cardiac and hepatic triglycerides were increased by all doses of STZ, in contrast, cardiac glycogen concentrations increased in a dose-dependent manner with increasing STZ concentrations. Cardiac glucose transporter 4 protein levels were decreased, whereas fatty acid metabolism-regulated proteins, including uncoupling protein 3 and pyruvate dehydrogenase (PDH) kinase 4, were increased with increasing doses of STZ. Cardiac PDH activity displayed a dose-dependent relationship between enzyme activity and STZ concentration. Cardiac insulin-stimulated glycolytic rates were decreased by 17% in 15 mg/kg STZ high-fat fed diabetic rats compared with control rats, with no effect on cardiac contractile function.ConclusionsHigh-fat feeding in combination with a low dose of STZ induced cardiac metabolic changes that mirror the decrease in glucose metabolism and increase in fat metabolism in diabetic patients. While low doses of 15-25 mg/kg STZ induced a type 2 diabetic phenotype, higher doses more closely recapitulated type 1 diabetes, demonstrating that the severity of diabetes can be modified according to the requirements of the study.

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Gender Differences in Cardiac Remodeling Induced by a High-Fat Diet and Lifelong, Low-Dose Cadmium Exposure.

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