Unraveling the mechanisms underlying cardiac dysfunction induced by metabolic disorders in rodent models

Metabolic disorders comprise a heterogeneous group of conditions characterized by alterations in cellular metabolism, often resulting from shifts in substrate utilization and energy balance. These disturbances frequently lead to mitochondrial dysfunction and accumulation of reactive oxygen species (ROS), promoting cellular damage and inflammation. Additionally, metabolic dysregulation, together with central mechanisms such as hypothalamic dysfunction, can alter autonomic nervous system activity. These mechanisms can converge on multiple organs, including the heart, potentially compromising their structural and functional integrity. Understanding the early mechanisms underlying these cardiometabolic disorders is crucial for mitigating disease progression and developing novel therapeutic strategies. In this PhD project, we investigated early alterations in cardiac function in two rodent models of metabolic diseases: Metabolic Syndrome (MetS) and Type 1 Diabetes Mellitus (T1DM). MetS, a condition characterized by obesity, hyperglycemia, dyslipidemia, and hypertension, is known to increase the risk of cardiovascular diseases, yet its direct effects on myocardial function and autonomic regulation remain incompletely understood. In our study, MetS was induced by long-term feeding of a Western Diet (WesD) in both wild-type and β1-/β2-adrenergic receptors knockout mice. While the diet produced a clear metabolic phenotype in both strains, cardiac alterations were observed only in wild-type mice. Specifically, WesD induced alterations in sinoatrial node activity, reduced heart rate variability, led to left ventricular hypertrophy and enhanced contractile properties of isolated cardiomyocytes in wild-type mice. In contrast, knockout mice lacking β-adrenergic receptors were protected from these changes, demonstrating that increased sympathetic activity is the main driver of early cardiac remodeling in MetS. These results highlight the critical role of sympathetic activation in mediating structural and functional cardiac adaptations under chronic metabolic stress. In T1DM, autoimmune destruction of pancreatic β-cells leads to hyperglycemia, dyslipidemia, mitochondrial dysfunction, and excessive ROS production, all contributing to the development of diabetic cardiomyopathy. In this study, T1DM was induced in rats by streptozotocin injection, and the potential cardioprotective effects of cerium oxide nanoparticles (CeO₂ NPs) were evaluated. Untreated diabetic rats exhibited systolic and diastolic dysfunction, with prolonged contraction and relaxation times at both the organ and cellular level. Treatment with CeO₂ NPs restored left ventricular contractile dynamics and improved the mechanical properties of isolated cardiomyocytes, partially normalizing calcium handling. The protective effects of these nanoparticles appear to arise from both direct and indirect mechanisms: CeO₂ NPs interact with proteins involved in cellular respiration, and directly scavenge ROS, while also promoting endogenous antioxidant defenses through activation of the circNCX1/Sirt1/Nrf2 signaling pathway. Furthermore, CeO₂ NPs improved plasma HDL functionality, enhancing reverse cholesterol transport and suggesting broader systemic benefits. Overall, this work demonstrates that early metabolic dysregulation induces measurable structural and functional changes in the heart, which are mediated by specific molecular and cellular pathways, including sympathetic activation in MetS and oxidative stress in T1DM. This study also provides compelling evidence that CeO₂ NPs can mitigate early diabetic cardiac complications by restoring redox balance, improving mitochondrial function, and enhancing endogenous antioxidant responses. These findings not only contribute to elucidating key mechanisms underlying cardiometabolic disorders but also highlight the potential of CeO₂ NPs as a promising adjuvant strategy for preventing myocardial damage in the early stages of diabetic cardiomyopathy.