Dilated Cardiomyopathy Mutations in Thin Filament Regulatory Proteins Reduce Contractility, Suppress Systolic Ca2+ & Activate NFAT & AKT Signalling.

Dilated Cardiomyopathy Mutations in Thin Filament Regulatory Proteins Reduce Contractility, Suppress Systolic Ca2+ &Activate NFAT &AKT Signalling. Am J Physiol Heart Circ Physiol. 2020 Jul 03;: Authors: Robinson P, Sparrow AJ, Patel S, Malinowska M, Reilly SN, Zhang YH, Casadei B, Watkins H, Redwood C Abstract Dilated cardiomyopathy (DCM) is clinically characterised by dilated ventricular cavities and reduced ejection fraction, leading to heart failure and increased thromboembolic risk. Mutations in thin filament regulatory proteins can cause DCM and have been shown in vitro to reduce contractility and myofilament Ca2+-affinity. In this work we have studied the functional consequences of mutations in cardiac troponin T (R131W), cardiac troponin I (K36Q) and α-tropomyosin (E40K) using adenovirally transduced isolated guinea pig left ventricular cardiomyocytes. We find significantly reduced fractional shortening with reduced systolic Ca2+. We also observe slowed contraction and Ca2+-reuptake times, which contrast with some findings in murine models of myofilament Ca2+-desensitisation. We also observe increased sarco-endoplasmic reticulum (SR) Ca2+ load and smaller fractional SR Ca2+ release. This corresponds to a reduction in SR Ca2+-ATPase activity and increase in Sodium-Calcium Exchanger activity. The disequilibrium of Ca2+ handling promotes dephosphorylation and nuclear translocation of the Nuclear-Factor-of-Activated T-cells (NFAT), with ...
Source: American Journal of Physiology. Heart and Circulatory Physiology - Category: Physiology Authors: Tags: Am J Physiol Heart Circ Physiol Source Type: research

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