Cardiac fibroblast injury in diabetes : new insights on the role of cytochromes P450 -

Abstract

Background: Diabetic cardiomyopathy (DCM), a serious complication of diabetes, is characterized by systolic and diastolic dysfunction, cardiomyocytes (CM) hypertrophy, and cellular matrix accumulation. Cardiac fibroblasts (CF), which make up around 70percent of a rat’s heart, play an important role in cardiac remodeling. DCM is associated with altered cytochrome P450 enzyme (CYP) expression and reactive oxygen species (ROS) production. It is known to re-induce the “fetal gene program” and activate autophagy pathway as a cell’s way of survival under stressful conditions. Aim: The present study aims to determine the effect of HET0016 or AUDA treatment on the biological output of the left ventricle (LV) and ROS generation. This work will investigate the mechanism of myocardial cell injury and how the treatments can alter the cross-talk between CYPs and oxidative stress and other possible mechanisms.Methods: 6 weeks streptozotocin (STZ) - induced diabetic rats received injections of either HET0016 or AUDA for 5 weeks. Afterwards, cardiac function and histological and biochemical parameters were measured. Echocardiography was performed to measure systolic function. Dihydroethidium (DHE) was used to assess intracellular ROS production levels. TUNEL assay was done to detect cellular hypertrophy and apoptotic cells. Western blot was performed to study the protein expression of: - and -myosin heavy chain (MHC), CYP2C11 and 4A1-A2-A3, beclin-1 and LC3B, and tau (p-S214). Histological alterations were measured using periodic acid Schiff (PAS) stain. Results: Treatment with HET0016 or AUDA reversed systolic dysfunction and prevented oxidative stress. AUDA treatment reversed “fetal gene program”. Type 1 diabetes mellitus (T1DM) increased autophagy; beclin-1 protein level was affected by HET0016, while LC3B protein level was affected by AUDA. It also increased tau hyperphosphorylation, while treatment with HET0016 or AUDA reduced tau hyperphosphorylation. Conclusion: Our results