• Lynn M Alaeddine, Frederic Harb, Maysaa Hamza, Batoul Dia, Nahed Mogharbil, Nadim S Azar, Mohamed H Noureldein, El KhouryMirellaMDepartment of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon., Ramzi Sabra, and Assaad A Eid.
• Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon; Department of Pharmacology and Toxicology, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon.
• Transl Res. 2021 Sep 1; 235: 85-101.

AbstractDiabetic cardiomyopathy (DCM) is a well-established complication of type 1 and type 2 diabetes associated with a high rate of morbidity and mortality. DCM is diagnosed at advanced and irreversible stages. Therefore, it is of utmost need to identify novel mechanistic pathways involved at early stages to prevent or reverse the development of DCM. In vivo experiments were performed on type 1 diabetic rats (T1DM). Functional and structural studies of the heart were executed and correlated with mechanistic assessments exploring the role of cytochromes P450 metabolites, the 20-hydroxyeicosatetraenoic acids (20-HETEs) and epoxyeicosatrienoic acids (EETs), and their crosstalk with other homeostatic signaling molecules. Our data displays that hyperglycemia results in CYP4A upregulation and CYP2C11 downregulation in the left ventricles (LV) of T1DM rats, paralleled by a differential alteration in their metabolites 20-HETEs (increased) and EETs (decreased). These changes are concomitant with reductions in cardiac outputs, LV hypertrophy, fibrosis, and increased activation of cardiac fetal and hypertrophic genes. Besides, pro-fibrotic cytokine TGF-ß overexpression and NADPH (Nox4) dependent-ROS overproduction are also correlated with the observed cardiac functional and structural modifications. Of interest, these observations are attenuated when T1DM rats are treated with 12-(3-adamantan-1-yl-ureido) dodecanoic acid (AUDA), which blocks EETs metabolism, or N-hydroxy-N'-(4-butyl-2-methylphenol)Formamidine (HET0016), which inhibits 20-HETEs formation. Taken together, our findings confer pioneering evidence about a potential interplay between CYP450-derived metabolites and Nox4/TGF-β axis leading to DCM. Pharmacologic interventions targeting the inhibition of 20-HETEs synthesis or the activation of EETs synthesis may offer novel therapeutic approaches to treat DCM.Copyright © 2021 Elsevier Inc. All rights reserved.

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