Tau Hyperphosphorylation: A Potential Molecular Mechanism for Diabetes-Induced Cardiac Dysfunction

Abstract

Background: Diabetic cardiomyopathy is one of the major macrovascular complications of diabetes characterized by the presence of abnormal cardiac structure and performance in the absence of other cardiac risk factors. Tau protein plays a key role in microtubule assembly and stabilization, as well as cytoskeletal network modification and organization. Considerable research highlights that the accumulation of tau protein into intracellular aggregates is a pathological feature of several neurodegenerative disorders including Alzheimer’s disease, Huntington’s disease, progressive supranuclear palsy, etc. In addition, our group has previously shown that Tau protein plays a major role in podocyte injury. Nonetheless, its function in diabetes-associated cardiac injury remains poorly investigated. Aim: In this study, we aim to assess the role of Tau hyperphosphorylation and aggregation in diabetes-induced cardiac dysfunction. We will also elucidate the interplay between Tau hyperphosphorylation and ROS production by the NADPH oxidases, specifically the CYP4A family of enzymes, known for its involvement in diabetic cardiomyopathy. Methods: Type 2 diabetic rodents (mice and rats) were used. Male Sprague-Dawley rats were divided into control, T2D rats, T2D rats treated with Tau inhibitor Lithium Chloride. In parallel FVB/NJ mice were divided into control, T2D mice, and T2D mice treated with CYP4A inhibitor HET0016. Cardiac functions, histological changes, biochemical and molecular alterations were assessed. Results: Inhibiting Tau phosphorylation with Lithium Chloride attenuated cardiac injury in the diabetic rats by significantly decreasing collagen and glycogen deposition in the heart. This was paralleled by an increase in the ejection fraction and fraction shortening %. Moreover, inhibiting Tau hyperphosphorylation attenuated ROS production and regulated the NADPH oxidase activity. Of interest, inhibiting 20-HETE production in diabetic mice using HET0016 modulated Tau phosphorylation and reversed diabetic cardiomyopathy, suggesting a potential crosstalk between Tau hyperphosphorylation and 20-HETE overproduction. Conclusion: Our results suggest that Tau/NADPH axis plays a pathogenic role in diabetes-induced cardiac dysfunction. Collectively, inhibiting either Tau phosphorylation or CYP4A-induced 20 HETE overproduction attenuates cardiac injury.