6B.09: EFFECT OF CANNABINOID RECEPTOR ACTIVATION ON ABERRANT MITOCHONDRIAL BIOENERGETICS IN HYPERTROPHIED CARDIAC MYOCYTES. (June 2015)

• Record Type: Journal Article
• Authors: Lu, Y.; Anderson, H.D.
• Is Part Of: Journal of hypertension. Volume 33(2015)Supplement 1
• Publication Date: 2015-06
• Subjects: Hypertension -- Periodicals; Hypertension -- Periodicals; 616.132005
• DOI: 10.1097/01.hjh.0000467564.80465.98
• Languages: English
• ISSNs: 1473-5598

Abstract

Abstract : Objective: We recently reported that activation of endocannabinoid receptors attenuates cardiac myocyte hypertrophy. Mitochondrial dysfunction has emerged as a critical determinant of aberrant myocyte energy production in cardiac hypertrophy. Thus, we determined endocannabinoid influence on mitochondrial function in the hypertrophied cardiac myocyte. Design and method: The experimental paradigm of hypertrophy in this study was neonatal rat cardiac myocytes treated with endothelin-1 (ET1; 0.1 μM). Ligand activation of cannabinoid receptors was achieved using CB13 (1 μM), a peripherally-restricted dual agonist of cannabinoid receptor subtypes CB1 and CB2. Changes in mitochondrial membrane potential (δψm) were assessed by fluorescence microscopy using the potential sensitive dye, JC-1. Biochemical modulators of mitochondrial function (i.e. peroxisome proliferator-activated receptor-γ coactivator 1α [PGC-1α - a driver of mitochondrial biogenesis], carnitine palmitoyl transferase 1β [CPT-1β - facilitator of fatty acid uptake], and AMP-activated protein kinase [AMPK – energy sensor]) were assessed by real-time PCR and western blotting. The Seahorse Bioscience XF24 Analyzer was used to measure fatty acid oxidation-related bioenergetics parameters. Results: ET1 caused mitochondrial aberrations which included membrane depolarization (δψm 80 ± 5% vs. control; p < 0.05), reduced PGC-1α (59 ± 7% vs. control; p < 0.01) and CPT-1β (81 ± 5% vs. control; p < 0.05) expression, as well as depressed palmitate-dependent respiration (basal/maximal/reserved respiration respectively: 81 ± 5%, 78 ± 4%, 74 ± 5% vs. control; p < 0.05), coupling efficiency (83 ± 6% vs. control; p < 0.05), and respiratory control ratio (79 ± 5% vs. control; p < 0.01). CB13 treatment restored all mitochondrial parameters to normal. Incidentally, CB13 activated AMPK via phosphorylation at Thr172 (354 ± 58% vs. control; p < 0.01), and the ability of CB13 to improve mitochondrial membrane potential and PGC-1α was abolished by compound C (a chemical inhibitor of AMPK) or shRNA knockdown of AMPK. These data suggest that AMPK contributes to the mitochondrial protective effects of CB13. Conclusions: The cardioprotective actions of liganded cannabinoid receptors extend to the mitochondrial level. Therefore, a cannabinoid-based treatment for cardiac disease remains a potential therapeutic strategy that warrants further study.