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: 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 Ca(2+) dependence of thin filament-activated myosin-S1-ATPase activity in a reconstituted, regulated, actomyosin system comparing wild-type 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 Ca(2+) sensitivity of the myofilaments containing the K206I variant was significantly increased, and when treated with 20 micromol/L (-)-epigallocatechin gallate (green tea) was restored back to wild-type levels in ATPase and force measurements. The K206I mutation impairs the ability of the troponin I to inhibit ATPase activity in the absence of calcium-bound human cardiac troponin C. The ability of calcium-bound human cardiac troponin C to neutralize the inhibition of K206I was greater than with wild-type TnI. CONCLUSIONS: Compromised interactions of K206I with actin and hcTnC may lead to impaired relaxation and HCM.
Journal Title: Circulation.Cardiovascular genetics
Volume: 8
Issue: 6
ISSN: 1942-3268; 1942-3268
Publisher: American Heart Association, Inc  
Journal Place: United States
Date Published: 2015
Start Page: 765
End Page: 773
Language: eng
DOI/URL:

10.1161/CIRCGENETICS.115.001234
Notes: LR: 20151218; CI: (c) 2015; GR: P01 HL062426/HL/NHLBI NIH HHS/United States; GR: R01 HL022231/HL/NHLBI NIH HHS/United States; JID: 101489144; NIHMS737263; OTO: NOTNLM; PMCR: 2016/12/01 00:00; 2015/01/14 [received]; 2015/11/06 [accepted]; 2015/11/09 [aheadofprint]; ppublish