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The Cardioprotective Actions of Phytochemicals
AuthorEvans, Levi W
AdvisorFerguson, Bradley S.
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We found that phytochemicals similarly and differentially regulated pathways and signal transduction cascades and that these actions were associated with an attenuation in agonist-induced cardiomyocyte hypertrophy (Chapter 2). Indeed, phenylephrine (PE) as an α1-adrenergic agonist observably increased phosphorylation of the mitogen activated protein kinases (MAPKs), extracellular regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38, as well as protein kinase C/D (PKC/D). These actions of PE were associated with an increase in cardiomyocyte hypertrophy, which is a common hallmark of heart failure. In contrast, Apigenin, Baicalein, Berberine Hydrochloride (BHCl) and Emodin blocked PE-induced cardiomyocyte hypertrophy, but not via cytotoxicity. Moreover, the overlapping and divergent effects of Apigenin, Baicalein, BHCl and Emodin on the MAPKs and PKC/D highlight our hypothesis in that phytochemicals work through several mechanisms, both similar and different and at different magnitudes (e.g., Emodin reduced phosphorylated-PKD more than Apigenin). Interestingly, Emodin completely abolished PKD phosphorylation while Apigenin, Baicalein andBHCl only attenuated PKD phosphorylation. Four phytochemicals, Apigenin, Baicalein, BHCl and Emodin, out of 18 were shown to be cardioprotective in Chapter 2. As our lab had previously found that these dietary compounds inhibited histone deacetylase (HDAC) activity, we next tested the postulate that Apigenin, Baicalein, BHCl and Emodin would attenuate HDAC activity in our cardiomyocyte experiments. Of the four, Emodin reduced HDAC activity the most. As HDAC inhibition is cardioprotective in experimental models of cardiovascular disease (CVD), our next task sought to elucidate the effects of Emodin on HDAC activity in the heart and if an Emodin-rich plant, rhubarb, behaved similarly to Emodin (Chapter 3). Firstly, our data showed that Emodin and rhubarb inhibited HDAC activity similarly in a test tube, as both inhibited HDAC activity in a fast-on slow-off manner. Additionally, rhubarb blocked intracellular- and receptor-mediated cardiomyocyte hypertrophy in a comparable manner to Emodin. Of interest, Emodin reduced HDAC activity concomitant with increased histone acetylation. As these epigenetic modification data suggest differential gene expression, we next compared and contrasted the effects of Emodin to a well-known HDAC inhibitor, Trichostatin A (TSA), on gene expression in cardiomyocytes. Our data showed that Emodin and TSA affected similar pathways but also different. These data make sense as phytochemicals, per Chapter 2, indeed act in multi-faceted manners, including via HDAC inhibition. Finally, we found that the effects of Emodin in cardiomyocytes were reflected in hypertensive mice. Thus, we found Emodin to be cardioprotective both in vitro and in vivo.Finally, we found it interesting that Emodin blocked hypertension-induced hypertrophy in mice despite lacking distribution to the heart. The microbiome has been implicated in heart failure. For example, germ-free mice infused with angiotensin II do not develop hypertension, hypertrophy nor fibrosis to the extent of their conventionally raised counterparts. Thus, we sought to characterize the effects of Emodin on hypertensive and healthy mice(Chapter 4). Our data linked the cardioprotective actions of Emodin in hypertensive mice with enrichment of Akkermansia (Chapter 4), a microbe that had previously been shown to be efficacious for diabetes and atherosclerosis. Intriguingly, healthy mice given Emodin via oral gavage also had enriched Akkermansiawhich suggests Emodin increases microbial abundance of Akkermansia independent of administration route. Other notable microbes that were enriched in healthy mice supplemented with Emodin included Roseburia and Allobaculum.