Activation of Cannabinoid Receptors Prevents Endothelin-1-induced Cardiac Myocyte Hypertrophy and Mitochondrial Dysfunction
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Date
2014-11
Authors
Lu, Yan
Journal Title
Journal ISSN
Volume Title
Publisher
Wolters Kluwer Health, Inc
Abstract
Objectives: Endocannabinoids are bioactive amides, esters, and ethers of long-chain polyunsaturated fatty acids that activate two cannabinoid receptors, CB1 and CB2. Evidence suggests that activation of the endocannabinoid pathway offers cardioprotection. Cardiac hypertrophy is a convergence point of risk factors for heart failure, and it is associated with aberrant mitochondrial function. We determined a role for endocannabinoids in attenuating endothelin-1 (ET1)-induced hypertrophy and mitochondrial dysfunction, as well as the signaling pathways involved.
Design and Methods: Cardiac myocyte hypertrophy was provoked by ET1 in isolated neonatal rat ventricular myocytes. Effects of four cannabinoid receptor agonists (anandamide, R-methanandamide, JWH-133 and CB-13) on hypertrophic markers (myocyte enlargement and hypertrophic gene expression) were assessed in the presence or absence of selective antagonists of CB1 or CB2 receptors. Mitochondrial function was evaluated by assessing changes in membrane permeability transition (calcein-AM), membrane potential (JC-1 dye), and mitochondrial bioenergetics related to fatty acid and glucose oxidation (seahorse XF24 analyzer). Molecular pathway components were identified by western blot and real-time PCR.
Results: Anandamide and its metabolically-inactive analogue, R-methanandamide, prevented ET1-induced increases in hypertrophic markers, and application of selective CB receptor antagonists revealed a distinct role of each receptor therein. Also, JWH-133, a selective CB2 agonist, and CB-13, a dual agonist of CB1/CB2 receptors with limited brain penetration, were investigated as strategies to theoretically avoid central CB1 receptor-mediated psychoactive effects. CB-13 attenuated all indicators of hypertrophy, whereas JWH-133 did not. The anti-hypertrophic actions of CB-13 were mediated by AMPK-eNOS crosstalk.
ET1 induced mitochondrial membrane depolarization in the presence of either palmitate or glucose as primary energy substrate, decreased mitochondrial bioenergetics and proteins related to fatty acid oxidation (i.e. PGC-1α, a driver of mitochondrial biogenesis, and CPT-1β, facilitator of fatty acid uptake), but did not affect glucose-related bioenergetics. CB-13 corrected all of these parameters, at least in part, via AMPK signaling.
Conclusions: Activation of cannabinoid receptors by CB-13, a peripherally-restricted agonist of CB1/CB2 receptors, offers protective effects on cardiac myocyte hypertrophy and its related mitochondrial disorders. Therefore, a cannabinoid-based treatment for cardiac disease represents a potential therapeutic strategy that warrants further study.
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Keywords
Cardiac hypertrophy, Cannabinoid receptors, Mitochondrial dysfunction, Bioenergetics, Endothelin-1, AMPK
Citation
Lu, Y., Akinwumi, B. C., Shao, Z., & Anderson, H. D. (2014). Ligand activation of cannabinoid receptors attenuates hypertrophy of neonatal rat cardiomyocytes. J Cardiovasc Pharmacol, 64(5), 420-430. doi:10.1097/FJC.0000000000000134