Dual cannabinoid receptor agonist, CB13, modulates signaling in ventricular hypertrophy and atrial remodeling

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Lee, Danielle
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Background: Structural, electrical, and metabolic remodeling contribute to cardiovascular disease, including atrial fibrillation (AF) and left ventricular hypertrophy (LVH). AF is the most common sustained cardiac arrhythmia, and LVH is the leading cause of heart failure. However, the molecular mechanisms to promote LVH, heart failure, and AF are poorly understood, giving rise to the possibility of novel therapeutic approaches. The endocannabinoid system (ECS) consists of endocannabinoids, cannabinoid receptors (CBR) and enzymes for synthesis and degradation. CBR agonists exert cardioprotective effects. By utilizing a dual CBR agonist, CB13 (1-naphthalenyl[4-(pentyloxy)-1-naphthalenyl]methanone), that has limited blood-brain barrier permeability, I aim to separate the potential advantageous peripheral cardioprotective effect from unwanted central effects. Hypothesis: CB13 prevents hypertrophy and mitochondrial dysfunction in ventricular cardiomyocytes, and this will extend into the stressed atria, and the hallmarks of AF therein. Results: Neonatal ventricular rat cardiomyocytes (NRVM) were used to determine the effect of CB13 on ventricular hypertrophy. CB13 prevented hypertrophy, restored mitochondrial membrane potential (ΔΨm) and prevented depression of fatty acid oxidation (FAO)-related bioenergetics when NRVM were exposed to the pro-hypertrophic compound, endothelin-1. CB13 activated AMPK and upregulated key signaling regulators of FAO. The effects of ECS activation were further investigated in the stressed myocardium by applying novel tachypacing techniques. CB13 did not alter chronotropic, dromotropic, or hemodynamic properties in non-paced hearts, preserved atrial effective refractory period in tachypaced hearts and activated AMPK. Lastly, neonatal rat atrial cardiomyocytes (NRAM) were used to determine underlying mechanisms in AF-related tachypaced remodeling. The anti-hypertrophic effect of CB13 and ability to preserve ΔΨm was demonstrated in NRAM. Additionally, AMPK and possibly Cx43 are major mediators for CB13-dependent cardioprotection. Conclusion: These findings demonstrate the protective effect of CB13 during hypertrophy, mitochondrial dysfunction and electrophysiological changes in vitro using NRAM and NRVM, and ex vivo using tachypaced SD rat hearts. Moreover, CB13 activates AMPK and may alter Cx43 expression. Due to the beneficial effects of CB13 in pathological hypertrophy and AF-related remodeling, these findings provide further insight into CBR agonists as a potential cardiovascular therapeutic strategy.
cardiomyocytes, hypertrophy, atrial fibrillation, cannabinoid