Novel Marine Compounds Modulate Mitochondrial Function in H9c2 Cells: Potential New Pharmaceutical Targets to Control Cardiac Metabolism

Abstract

IntroductionThe global burden of cardiovascular disease is increasing and is the leading cause of morbidity and mortality worldwide. As the heart is a highly metabolic organ, mitochondrial health is critical to normal cardiac function and is compromised in a number of cardiac diseases. Therefore, new pharmaceutical agents and screening tools to modulate and evaluate cardiac metabolism may offer novel therapeutics for cardiovascular disease.MethodsA number of marine compounds have been curated over the years by faculty at the Scripps Institution of Oceanography. Chemical structures have been largely elucidated through nuclear magnetic resonance spectroscopy and mass spectrometry, and these have been broadly available for biological screening through the UCSD Center for Compound Resources. Seventy‐three promising marine compounds were evaluated by application on H9c2 rat cardiomyoblasts while measuring oxygen consumption rate and extracellular acidification rate with a Seahorse XF96 extracellular flux analyzer. Mitochondrial metabolism was tested at a range of compound concentrations (0.1–1.6 mM). Subsequently, dose response curves of compounds that showed biological activity in the initial screen were performed. Dose response assay concentrations ranged from 0.01 nM to 3 μM with vehicle only as the control.ResultsEight compounds showed significant dose dependent alterations in mitochondrial metabolism in the initial screen. Dose response assays of glycospongosine revealed an increase in ATP linked‐maximal respiration ratio. In contrast, higher glycospongosine concentrations led to a gradual dose dependent decrease in reserve capacity. Injection of leptochelin A first increased basal respiration of the cardiomyoblasts, after the first increase, basal respiration gradually decreased. Increasing concentrations of honaucin A lowered the maximal mitochondrial respiration dose dependently. In addition, kabiramide C decreased maximal respiration normalized to basal respiration.ConclusionWe present here the results of screening multiple marine natural products in a cell based metabolic assay. Marine compounds have a demonstrated potential to modulate cardiac metabolism in a variety of settings; however, further research in disease models is necessary to determine if such modulation via these compounds is beneficial or harmful to cardiovascular disease.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.