Abstract
The prevalence of diabetic metabolic derangement (DMetD) has increased dramatically over the last decades. Although there is increasing evidence that DMetD is associated with cardiac dysfunction, the early DMetD-induced myocardial alterations remain incompletely understood. Here, we studied early DMetD-related cardiac changes in a clinically relevant large animal model. DMetD was established in adult male Göttingen miniswine by streptozotocin injections and a high-fat, high-sugar diet, while control animals remained on normal pig chow. Five months later left ventricular (LV) function was assessed by echocardiography and hemodynamic measurements, followed by comprehensive biochemical, molecular and histological analyses. Robust DMetD developed, evidenced by hyperglycemia, hypercholesterolemia and hypertriglyceridemia. DMetD resulted in altered LV nitroso-redox balance, increased superoxide production—principally due to endothelial nitric oxide synthase (eNOS) uncoupling—reduced nitric oxide (NO) production, alterations in myocardial gene-expression—particularly genes related to glucose and fatty acid metabolism—and mitochondrial dysfunction. These abnormalities were accompanied by increased passive force of isolated cardiomyocytes, and impaired LV diastolic function, evidenced by reduced LV peak untwist velocity and increased E/e′. However, LV weight, volume, collagen content, and cardiomyocyte cross-sectional area were unchanged at this stage of DMetD. In conclusion, DMetD, in a clinically relevant large-animal model results in myocardial oxidative stress, eNOS uncoupling and reduced NO production, together with an altered metabolic gene expression profile and mitochondrial dysfunction. These molecular alterations are associated with stiffening of the cardiomyocytes and early diastolic dysfunction before any structural cardiac remodeling occurs. Therapies should be directed to ameliorate these early DMetD-induced myocardial changes to prevent the development of overt cardiac failure.
Highlights
The prevalence of diabetic metabolic derangement (DMetD) has increased dramatically over the last decades
left ventricular (LV) function was assessed at baseline and 5 months after induction of DMetD, and myocardial tissue was comprehensively analyzed for oxidative stress and nitric oxide (NO) production, mitochondrial function, cardiomyocyte function, collagen content, and global LV remodeling and function, as well as for genomewide gene expression profile
Five months of DMetD resulted in hyperglycemia (p < 0.05), hypercholesterolemia (p < 0.05) and hypertriglyceridemia (p < 0.05), while no significant differences in body weight were observed between the groups (Table 1)
Summary
The prevalence of diabetic metabolic derangement (DMetD) has increased dramatically over the last decades. DMetD, in a clinically relevant large-animal model results in myocardial oxidative stress, eNOS uncoupling and reduced NO production, together with an altered metabolic gene expression profile and mitochondrial dysfunction These molecular alterations are associated with stiffening of the cardiomyocytes and early diastolic dysfunction before any Research School COEUR, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands. Our study shows that DMetD results in myocardial oxidative stress, endothelial nitric oxide synthase (eNOS) uncoupling and reduced NO production together with mitochondrial dysfunction and alterations in metabolic gene expression profile These abnormalities are associated with impaired LV relaxation, at a time when cardiac structural remodeling at either the global LV or myocardial tissue level is still absent
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