Melinda E. Tóth, Márta Sárközy, Gergő Szűcs, Brigitta Dukay, Petra Hajdu, Ágnes Zvara, László G. Puskás, Gábor J. Szebeni, Zsófia Ruppert, Csaba Csonka, Ferenc Kovács, András Kriston, Péter Horváth, Bence Kővári, Gábor Cserni, Tamás Csont, Miklós Sántha, and Institute for Molecular Medicine Finland
Background Metabolic syndrome (MetS) refers to a cluster of co-existing cardio-metabolic risk factors, including visceral obesity, dyslipidemia, hyperglycemia with insulin resistance, and hypertension. As there is a close link between MetS and cardiovascular diseases, we aimed to investigate the sex-based differences in MetS-associated heart failure (HF) and cardiovascular response to regular exercise training (ET). Methods High-fat diet-fed male and female APOB-100 transgenic (HFD/APOB-100, 3 months) mice were used as MetS models, and age- and sex-matched C57BL/6 wild-type mice on standard diet served as healthy controls (SD/WT). Both the SD/WT and HFD/APOB-100 mice were divided into sedentary and ET groups, the latter running on a treadmill (0.9 km/h) for 45 min 5 times per week for 7 months. At month 9, transthoracic echocardiography was performed to monitor cardiac function and morphology. At the termination of the experiment at month 10, blood was collected for serum low-density lipoprotein (LDL)- and high-density lipoprotein (HDL)-cholesterol measurements and homeostatic assessment model for insulin resistance (HOMA-IR) calculation. Cardiomyocyte hypertrophy and fibrosis were assessed by histology. Left ventricular expressions of selected genes associated with metabolism, inflammation, and stress response were investigated by qPCR. Results Both HFD/APOB-100 males and females developed obesity and hypercholesterolemia; however, only males showed insulin resistance. ET did not change these metabolic parameters. HFD/APOB-100 males showed echocardiographic signs of mild HF with dilated ventricles and thinner walls, whereas females presented the beginning of left ventricular hypertrophy. In response to ET, SD/WT males developed increased left ventricular volumes, whereas females responded with physiologic hypertrophy. Exercise-trained HFD/APOB-100 males presented worsening HF with reduced ejection fraction; however, ET did not change the ejection fraction and reversed the echocardiographic signs of left ventricular hypertrophy in HFD/APOB-100 females. The left ventricular expression of the leptin receptor was higher in females than males in the SD/WT groups. Left ventricular expression levels of stress response-related genes were higher in the exercise-trained HFD/APOB-100 males and exercise-trained SD/WT females than exercise-trained SD/WT males. Conclusions HFD/APOB-100 mice showed sex-specific cardiovascular responses to MetS and ET; however, left ventricular gene expressions were similar between the groups except for leptin receptor and several stress response-related genes., Highlights Both HFD/APOB-100 males and females developed obesity and hypercholesterolemia; however, only males presented insulin resistance. Exercise training did not change these metabolic parameters significantly.HFD/APOB-100 males showed echocardiographic signs of mild heart failure with thinner walls and dilated ventricles, whereas females developed a starting left ventricular hypertrophy assessed by echocardiography and histology.In response to exercise training, SD/WT males developed increased left ventricular volumes, and females presented physiologic hypertrophy.Exercise-trained HFD/APOB-100 males presented worsening heart failure with reduced ejection fraction. On the contrary, exercise-trained HFD/APOB-100 females reversed the echocardiographic signs of left ventricular hypertrophy.Sex, metabolic syndrome, and exercise training alter the gene expression pattern of the myocardium, which may be involved in the development of sex-specific cardiac alterations in the state of metabolic syndrome or to exercise training.