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

Chad M. Warren, Chehade N. Karam, Beata M. Wolska, Tomoyoshi Kobayashi, Pieter P. De Tombe, Grace M. Arteaga, J. Martijn Bos, Michael J. Ackerman, R. John Solaro

Research output: Contribution to journalArticle

13 Scopus citations


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 HCMassociated 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 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 Ca2+ sensitivity of the myofilaments containing the K206I variant was significantly increased, and when treated with 20 ìmol/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.

Original languageEnglish (US)
Pages (from-to)765-773
Number of pages9
JournalCirculation: Cardiovascular Genetics
Issue number6
StatePublished - Dec 1 2015


  • Actin
  • actomyosin
  • calcium
  • echocardiography
  • troponin

ASJC Scopus subject areas

  • Genetics
  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)

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