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Currently, greater than one billion people are overweight and 30% of the population is obese. Several structural and functional changes of the heart have often been associated with human obesity. Experimental models for high-fat diets have been used to study the relationship between obesity and the heart. Myocardial calcium (Ca) handling has been extensively studied in several experimental models and has often been shown to be related to cardiac dysfunction. However, few studies have evaluated the relationship between the duration of exposure to obesity and a high-fat diet, and mRNA and proteins involved in homeostasis of myocardial Ca. Some studies have reported the influence of thyroid hormones on these proteins, which may cause changes in cardiac contraction and relaxation. The main objective of the current study was to test the hypothesis that the increased duration of exposure to obesity leads to a reduction in the expression and/or phosphorylation of proteins and mRNA levels related to myocardial Ca handling. This study had, as additional objective, to verify if the decrease in mRNA expression was accompanied by a reduction in thyroid hormone levels. The periods of exposure to a high-fat diet used in this study were effective in promoting obesity since the adiposity index used to characterize animals as obese was 79.5%, 82%, and 69.5% higher than controls after 15, 30, and 45 weeks, respectively. The duration of exposure to a high-fat diet did not change the total body fat between the obese groups. This result indicates that there was not an increase in the intensity of obesity over time. In this study, some co-morbidities often associated with experimental obesity existed, such as glucose intolerance, insulin resistance, hyperinsulinemia, hyperleptinemia, and dyslipidemia; however, the co-morbidities were not associated with changes in systolic blood pressure. Obesity promoted an increase in serum TSH over time and a decrease in T4 levels accompanied by elevated serum concentrations of T3. The cardiac structure results post-death showed that obesity caused an increase in the heart, and right ventricular and atrium weights at the 3 evaluation times, although the change in heart weight at 45 weeks was not statistically significant (p = 0.052). In addition, there was left ventricular remodeling at 15 and 30 weeks. However, the analysis of the cross-sectional area of myocytes showed an increase in obesity at 30 weeks. Although obesity altered the mRNA levels of the ryanodine receptor (RyR) and L-type Ca channels between obese and control groups over time, this change was not shown in the protein expression of L-type Ca channels. While obesity at the 15 and 45 weeks resulted in a reduction of mRNA levels of Ca ATP-ase of sarcoplasmic reticulum (SERCA), Na/Ca exchanger (NCX), and calsequestrin (CSQ) in relation to respective controls, in the 30 week of obesity the mRNA levels of SERCA, NCX, and CSQ were higher than C30. However, the change in mRNA was not accompanied by changes in SERCA and CSQ protein expression. The mRNA levels of phospholamban (PLB) were decreased after 15 weeks of obesity and elevated at 30 weeks between the groups. The protein levels of PLB, PLB phosphorylation at threonine-17 (pPLB thr17), and the ratio between pPLB thr17 and PLB was not changed due to obesity. The main finding of this study was that obesity, after 15 and 30 weeks, resulted in decreased levels of PLB phosphorylation at serine-16 (pPPLB ser16). The correlation analysis showed that there was no significant association between the levels of T3 mRNA and protein of myocardial Ca handling. An important fact observed in this study was the difference in behavior between the levels of mRNA and protein expression. While the mRNA varied depending on the experimental treatment and time of exposure, the proteins were equal among the groups and times of exposure of obesity. In conclusion, the time of exposure to obesity promotes different responses in mRNA expression and modifies only the pPPLB ser16. Thyroid hormone levels do not influence the expression of mRNA and proteins of myocardial Ca handling.

Influência do tempo de exposição à obesidade sobre a expressão gênica e protéica do sistema regulador do trânsito de cálcio miocárdico