A Green Tea Catechin Normalizes the Enhanced Ca2+ Sensitivity of Myofilaments Regulated by a Hypertrophic Cardiomyopathy Associated Mutation in Human Cardiac Troponin I (K206I) Journal Article

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Authors: Warren, C. M.; Karam, C. N.; Wolska, B. M.; Kobayashi, T.; de Tombe, P. P.; Arteaga, G. M.; Bos, J. M.; Ackerman, M. J.; Solaro, R. J.
Article Title: A Green Tea Catechin Normalizes the Enhanced Ca2+ Sensitivity of Myofilaments Regulated by a Hypertrophic Cardiomyopathy Associated Mutation in Human Cardiac Troponin I (K206I)
Abstract: BACKGROUND: -Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease characterized by thickening of ventricular walls and decreased left ventricular chamber volume. The majority of HCM-associated mutations are found in genes encoding sarcomere proteins. Herein, we set out to functionally characterize a novel HCM-associated mutation (K206I-TNNI3), and elucidate the mechanism of dysfunction at the level of myofilament proteins. METHODS AND RESULTS: -The male index case was diagnosed with HCM after an out-of-hospital cardiac arrest which was followed by comprehensive clinical evaluation, transthoracic echocardiography, and clinical genetic testing. To determine molecular mechanism(s) of the mutant human cardiac troponin I (K206I), we tested the Ca2+ dependence of thin filament-activated myosin-S1-ATPase activity in a reconstituted, regulated, actomyosin system comparing wildtype human troponin complex, 50% mix of K206I/wildtype, or 100% K206I. We also exchanged native troponin detergent extracted fibers with reconstituted troponin containing either wildtype or a 65% mix of K206I/wildtype, and measured force generation. The Ca2+ sensitivity of the myofilaments containing the K206I variant was significantly increased, and when treated with 20 muM EGCG (green tea) was restored back to wildtype levels in ATPase and force measurements. The K206I mutation impairs the ability of the troponin I to inhibit ATPase activity in the absence of Ca-hcTnC (calcium-bound-human cardiac troponin C). The ability of Ca-hcTnC to neutralize the inhibition of K206I was greater than with wildtype TnI. CONCLUSIONS: -Compromised interactions of K206I with actin and hcTnC may lead to impaired relaxation and HCM.
Journal Title: Circulation.Cardiovascular genetics
ISSN: 1942-3268; 1942-3268
Publisher: Unknown  
Date Published: 2015
Language: ENG
DOI/URL:

CIRCGENETICS.115.001234
Notes: LR: 20151116; GR: P01 HL062426/HL/NHLBI NIH HHS/United States; GR: R01 HL022231/HL/NHLBI NIH HHS/United States; JID: 101489144; OTO: NOTNLM; aheadofprint