Abstract 3829: Cannabidiol Attenuates Myocardial Dysfunction, Fibrosis, Inflammation, Cell Death and Interrelated Signaling Pathways Associated With Diabetic Cardiomyopathy
A nonpsychoactive component of Cannabis sativa plant, cannabidiol (CBD), which has recently been approved for the treatment of inflammation, pain, and spasticity associated with multiple sclerosis in patients, exerts numerous beneficial effects unrelated to the activation of cannabinoid receptors. In this study, we have investigated the effects of CBD on the course of myocardial dysfunction, inflammation, oxidative/nitrosative stress, cell death and interrelated signaling pathways, using a mouse model of type I diabetic cardiomyopathy or primary human cardiomyocytes exposed to high glucose. Control and diabetic mice were treated with CBD or vehicle starting from 2 weeks following the establishment of diabetes for 10 weeks or 8 weeks after the establishment of diabetes for 4 weeks. Left ventricular systolic and diastolic functions were determined using pressure-volume conductance system 8 or 12 weeks after established diabetes. Diabetic cardiomyopathy was characterized by declined diastolic and systolic myocardial performance associated with increased myocardial lipid peroxidation, 4-HNE and 3-nitrotyrosine accumulation, NFkappaB and MAPK (JNK and p-38) activation, enhanced expression of adhesion molecules (ICAM-1, VCAM-1), TNFalpha, iNOS, markers of fibrosis (TGFbeta, CTGF, fibronectin, collagen-1, MMP-2 and MMP-9), and augmented cell death (caspase 3/7 and PARP activity and chromatin fragmentation). Remarkably, both pre- or post treatment with CBD attenuated myocardial dysfunction, cardiac fibrosis, oxidative/nitrosative stress, inflammation, cell death, and interrelated signaling pathways. Furthermore, CBD also attenuated the high glucose-induced increased reactive oxygen and nitrogen species generation (both cytosolic and mitochondrial), NFkappa B activation and cell death in primary human cardiomyocytes. Collectively, these results coupled with the excellent safety and tolerability profile of cannabidiol in humans, strongly suggest that it may have tremendous therapeutic potential in the treatment of diabetic complications by attenuating oxidative/nitrosative stress, cell death and fibrosis.