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Title: Effects of in vivo green tea extract administration on contractile performance and mithocondrial function of ventricular cardiomyocytes, in healty and diabetic rats
Authors: Vilella, Rocchina
Issue Date: Mar-2021
Publisher: Università degli Studi di Parma. Dipartimento di Medicina e chirurgia
Document Type: Doctoral thesis
Abstract: Green tea, produced from the dried leaves of the Camellia sinensis plant, is one of the most widely consumed beverage in the world. Epidemiological, clinical, and experimental studies have established a close relationship between the green tea intake and the risk reduction of several pathological conditions including cardiovascular diseases (CVDs). The predominant and medically relevant active components of green tea are the polyphenols, among which catechins (about 80%) are the most bioactive compounds. There are four main types of green tea catechins (GTCs): epigallocatechin-3-gallate (EGCG), which is the main molecular component known to exert a wide range of biological activities, epigallocatechin (EGC), epicatechin-3-gallate (ECG), and epicatechin (EC). The underlying mechanisms by which GTCs exert cardioprotective effects include antioxidant, anti-proliferative, anti-inflammatory, and anti-thrombogenic actions. Previous experimental studies have documented that GTCs, especially EGCG, are able to attenuate reperfusion-induced myocardial damage, cardiac hypertrophic response to pressure-overload, sympathetic hyperactivity in hypertension, and ventricular dysfunction in several cardiomyopathies. Moreover, mechanistic studies have demonstrated that green tea polyphenols may influence many aspects of cardiovascular function by their interaction with a list of intracellular target, such as several ion channels and ion exchangers (Na+/K+-ATPase, Na+/H+ and Na+/Ca2+), intracellular Ca2+ storage, and sarcomeric troponin protein. However, most studies refer to the effects of acute exposure to GTCs and have been performed on cell lines, perfused rat hearts, isolated cardiomyocytes, subcellular cardiomyocyte organelles, and in silico models. Conversely, studies showing potential positive effects on normal heart of in vivo long term administration of GTCs, are still lacking. On the basis of these evidence, the first part of the study was aimed at evaluating the effects of oral administration of a standardized green tea extract (GTE, 90mg/day in 40ml of tap water for 28 days), in comparison with its major component EGCG, given at the equivalent amount that would be in the entirety of GTE (63 mg/day in 40ml of tap water for 28 days), on cardiac function. We addressed this issue following an experimental approach which involved in vivo and ex vivo measurement of contractile properties in healthy male Wistar rats, focusing on the underlying molecular mechanism and mitochondrial bioenergetics. GTE and EGCG cardiomyocytes exhibited a significant improvement of cellular bioenergetics when compared to controls as shown by the maximal mitochondrial respiration rate and the steady-state ATP content. The improvement of the mitochondrial function was associated with increased levels of oxidative phosphorylation complexes, whereas the cellular mitochondrial mass was unchanged. However, only the GTE supplementation improved cardiomyocyte mechanics and intracellular calcium dynamics, by lowering the expression of total phospholamban (PLB), which led to an increase of both the phosphorylated-PLB/PLB and the sarco-endoplasmic reticulum calcium ATPase/PLB ratios, usually coupled with enhanced cardiac mechanical performance. In conclusion, we showed that both GTE and EGCG improve cardiomyocyte mitochondrial function by enhancing the OXPHOS complexes levels in healthy rats. Nevertheless, only in vivo administration of GTE ameliorated cardiomyocyte mechanics by targeting excitation-contraction key proteins. The lack of effects on cellular mechanics by pure EGCG, given at the same dosage contained in the green tea extract, suggests that the combination of all the catechins contained in the standardized GTE is likely needed to enhance the cardiomyocyte contractile efficiency. Due to GTE effects on mitochondrial function and the level of proteins involved in excitation-contraction coupling, we advanced the hypothesis that this standardized green tea extract might be a valuable adjuvant tool for counteracting the occurrences and/or progression of different cardiomyopathies, including diabetic cardiomyopathy, in which mitochondrial dysfunction, reduced energy availability, and changes in the expression and/or activity of the proteins responsible for the cardiomyocyte contractile efficiency, constitute early pathogenic factors. For this purpose, the second part of this study was focused on investigating the ability of early GTE administration to prevent the development of cardiomyocyte contractile dysfunction induced by a short period of hyperglycemia. To specifically address this issue, cardiomyocyte contractile properties and intracellular calcium dynamics were measured in a rat model of early diabetes, after in vivo administration of GTE (90mg/day in 50ml of tap water for 21 days). GTE treatment in diabetic rats induced an almost complete recovery of cellular mechanical properties and intracellular calcium dynamics, markedly worsened in unloaded ventricular myocytes isolated from diabetic hearts, assuming values comparable to controls. Our preliminary results support the idea that green tea dietary polyphenols can constitute a new therapeutic adjuvant strategy capable of preventing the initial myocardial damage occurring in the diabetic heart and its progression towards an overt pathological condition. However, additional studies will be necessary to (i) elucidate the mechanisms by which GTE modulate the expression and/or activity of the main molecules involved in the excitation-contraction processes and (ii) better evaluate GTE effects on mitochondrial function and dynamics, widely impaired in diabetic cardiomyopathy.
Appears in Collections:Medicina molecolare, tesi di dottorato

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