Biological actions of green tea catechins on cardiac troponin C

Abstract

BACKGROUND AND PURPOSE Catechins, biologically active polyphenols in green tea, are known to have a protective effect against cardiovascular diseases. In this study, we investigated direct actions of green tea catechins on cardiac muscle function to explore their uses as potential drugs for cardiac muscle disease. EXPERIMENTAL APPROACH The effects of catechins were systematically investigated on the force‐pCa relationship in skinned cardiac muscle fibres to determine their direct effects on cardiac myofilament contractility. The mechanisms of action of effective catechins were investigated using troponin exchange techniques, quartz crystal microbalance, nuclear magnetic resonance and a transgenic mouse model. KEY RESULTS (‐)‐Epicatechin‐3‐gallate (ECg) and (‐)‐epigallocatechin‐3‐gallate (EGCg), but not their stereoismers (‐)‐catechin‐3‐gallate and (‐)‐gallocatechin‐3‐gallate, decreased cardiac myofilament Ca2+ sensitivity probably through its interaction with cardiac troponin C. EGCg restored cardiac output in isolated working hearts by improving diastolic dysfunction caused by increased myofilament Ca2+ sensitivity in a mouse model of hypertrophic cardiomyopathy. CONCLUSIONS AND IMPLICATIONS The green tea catechins, ECg and EGCg, are Ca2+ desensitizers acting through binding to cardiac troponin C. These compounds might be useful compounds for the development of therapeutic agents to treat the hypertrophic cardiomyopathy caused by increased Ca2+ sensitivity of cardiac myofilaments.

Solution Structure of Human Cardiac Troponin C in Complex with the Green Tea Polyphenol, (−)-Epigallocatechin 3-Gallate

“…Contrary to W7, however, we illustrate by NMR that EGCg binds to the C-domain of cTnC preferentially. This observation has also been shown by fluorometry and NMR spectroscopy (28,30).…”

“…NMR has been utilized to show that W7 binds both the C-and N-terminal domains of cTnC in the absence of cTnI (43); however, in the presence of cTnI-(34 -71) and cTnI-(128 -163), W7 associates exclusively in the N-terminal domain of cTnC (52). Similarly, EGCg has been identified by the preliminary study of Tadano et al (30) and by the recent work of Liou et al (28) to reduce the Ca 2ϩ sensitivity of myofibrillar ATPase activity in cardiac myofibrils. Contrary to W7, however, we illustrate by NMR that EGCg binds to the C-domain of cTnC preferentially.…”

Coordinated Regulation of Murine Cardiomyocyte Contractility by Nanomolar (−)-Epigallocatechin-3-Gallate, the Major Green Tea Catechin

“…However, the conclusions reached regarding the molecular targets responsible for the observed EGCG effects diverged. A recent study indicates that EGCG concentrations of 30 M or higher cause a negative inotropic effect by binding to troponin C and reducing myofilament Ca 2ϩ sensitivity (Tadano et al, 2010). In the present study, we identify the cardiac SR Ca 2ϩ release channel, RyR2, as one of the novel and selective targets of EGCG.…”

Sarcomere neutralization in inherited cardiomyopathy: small-molecule proof-of-concept to correct hyper-Ca2+-sensitive myofilaments

“…EGCG and resveratrol have been suggested to bind to cTnC and decrease Ca 2ϩ sensitivity (19,26,28). EGCG was recently shown to improve diastolic dysfunction in HCM and RCM mouse models, suggesting that desensitization of the myofilament is therapeutically relevant (10,32,35). In a cTnT model of HCM, EGCG improved relaxation in working hearts and improved Ca 2ϩ transient kinetics in cardiac myocytes (32).…”

“…EGCG was recently shown to improve diastolic dysfunction in HCM and RCM mouse models, suggesting that desensitization of the myofilament is therapeutically relevant (10,32,35). In a cTnT model of HCM, EGCG improved relaxation in working hearts and improved Ca 2ϩ transient kinetics in cardiac myocytes (32). In a cTnI RCM model, EGCG improved diastolic parameters in echocardiography of whole animals treated chronically as well as acute treatment in cardiac myocytes improved relaxation (35).…”