Abstract 9373: Cinnamamide Derivative Reduces Left Ventricular Dysfunction by Modulating Mitochondrial Dynamics in Prediabetic Rats

Abstract

Introduction: Chronic high-fat diet (HFD) consumption induces prediabetes via increased systemic inflammation by activating myeloid differentiation factor 2 (MD2)/toll-like receptor 4 pathway, resulting in left ventricular (LV) dysfunction. Cinnamamide derivative was shown previously to reduce inflammation in lipopolysaccharide-induced septic mice by targeting MD2. However, the effects of cinnamamide derivative, 2i-10, on the LV function in prediabetes are not known. Hypothesis: 2i-10 improves LV function in prediabetic rats by reducing cardiac inflammation, mitochondrial dysfunction, and mitochondrial dynamics imbalance. Methods: Prediabetic rats were induced by feeding HFD for 12 weeks, and were divided into 3 groups; vehicle, 2i-10 (40 mg/kg), or metformin (300 mg/kg). Normal diet fed rats received vehicle. Rats orally received their assigned treatment for 4 weeks. Then, LV function, cardiac inflammation, and mitochondrial function and dynamics were examined. Results: Prediabetic rats had impaired LV function, as shown by reduced %LV ejection fraction. Moreover, impaired mitochondrial function and dynamics were observed, as shown by increased reactive oxygen species (ROS), mitochondrial depolarization, swelling, increased mitochondrial fission (p-Drp1/Drp1) and decreased mitochondrial fusion (OPA1). NF-κB phosphorylation was increased in these rats, indicating inflammation. Treatment with 2i-10 significantly reduced cardiac inflammation, mitochondrial dysfunction, mitochondrial dynamic imbalance, and improved LV function in prediabetic rats (Fig 1). Similar benefits were observed in metformin-treated rats. Conclusions: Chronic treatment with 2i-10, effectively suppressed cardiac inflammation, mitochondrial dysfunction and mitochondrial dynamics imbalance, leading to improved LV function in prediabetic rats. These findings suggest that targeting MD2 could be a novel treatment to protect the heart in prediabetes.