title: Epigallocatechin-3-Gallate Accelerates Relaxation and Ca2+Transient Decay and Desensitizes Myofilaments in Healthy andMybpc3-Targeted Knock-in Cardiomyopathic Mice.
abstract: Background:Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac muscle disease with left ventricular hypertrophy, interstitial fibrosis and diastolic dysfunction. Increased myofilament Ca2+sensitivity could be the underlying cause of diastolic dysfunction. Epigallocatechin-3-gallate (EGCg), a catechin found in green tea, has been reported to decrease myofilament Ca2+sensitivity in HCM models with troponin mutations. However, whether this is also the case for HCM-associated thick filament mutations is not known. Therefore, we evaluated whether EGCg affects the behavior of cardiomyocytes and myofilaments of an HCM mouse model carrying a gene mutation in cardiac myosin-binding protein C and exhibiting both increased myofilament Ca2+sensitivity and diastolic dysfunction.Methods and Results:Acute effects of EGCg were tested on fractional sarcomere shortening and Ca2+transients in intact ventricular myocytes and on force-Ca2+relationship of skinned ventricular muscle strips isolated fromMybpc3-targeted knock-in (KI) and wild-type (WT) mice. Fractional sarcomere shortening and Ca2+transients were analyzed at 37°C under 1-Hz pacing in the absence or presence of EGCg (1.8 μM). At baseline and in the absence of Fura-2, KI cardiomyocytes displayed lower diastolic sarcomere length, higher fractional sarcomere shortening, longer time to peak shortening and time to 50% relengthening than WT cardiomyocytes. In WT and KI neither diastolic sarcomere length nor fractional sarcomere shortening were influenced by EGCg treatment, but relaxation time was reduced, to a greater extent in KI cells. EGCg shortened time to peak Ca2+and Ca2+transient decay in Fura-2-loaded WT and KI cardiomyocytes. EGCg did not influence phosphorylation of phospholamban. In skinned cardiac muscle strips, EGCg (30 μM) decreased Ca2+sensitivity in both groups.Conclusion:EGCg hastened relaxation and Ca2+transient decay to a larger extent in KI than in WT cardiomyocytes. This effect could be partially explained by myofilament Ca2+desensitization.
authors.affiliation: Cardiovascular Research Center, Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-EppendorfHamburg, Germany; German Centre for Cardiovascular Research (DZHK)Hamburg, Germany.
authors.forename: Felix W
authors.initials: FW
authors.lastname: Friedrich
authors.affiliation: Cardiovascular Research Center, Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-EppendorfHamburg, Germany; German Centre for Cardiovascular Research (DZHK)Hamburg, Germany.
authors.forename: Frederik
authors.initials: F
authors.lastname: Flenner
authors.affiliation: Cardiovascular Research Center, Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-EppendorfHamburg, Germany; German Centre for Cardiovascular Research (DZHK)Hamburg, Germany.
authors.forename: Mahtab
authors.initials: M
authors.lastname: Nasib
authors.affiliation: Cardiovascular Research Center, Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-EppendorfHamburg, Germany; German Centre for Cardiovascular Research (DZHK)Hamburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Eschenhagen
authors.affiliation: Cardiovascular Research Center, Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-EppendorfHamburg, Germany; German Centre for Cardiovascular Research (DZHK)Hamburg, Germany.
authors.forename: Lucie
authors.initials: L
authors.lastname: Carrier
keywords: Ca2+ transient; Mybpc3; epigallocatechin-3-gallate; hypertrophic cardiomyopathy; myofilament Ca2+ sensitivity; relaxation