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GSK-3β Localizes to the Cardiac Z-Disc to Maintain Length Dependent Activation
BackgroundAltered kinase localization is gaining appreciation as a mechanism of cardiovascular disease. Previous work suggests GSK-3β (glycogen synthase kinase 3β) localizes to and regulates contractile function of the myofilament. We aimed to discover GSK-3β's in vivo role in regulating myofilament function, the mechanisms involved, and the translational relevance.MethodsInducible cardiomyocyte-specific GSK-3β knockout mice and left ventricular myocardium from nonfailing and failing human hearts were studied.ResultsSkinned cardiomyocytes from knockout mice failed to exhibit calcium sensitization with stretch indicating a loss of length-dependent activation (LDA), the mechanism underlying the Frank-Starling Law. Titin acts as a length sensor for LDA, and knockout mice had decreased titin stiffness compared with control mice, explaining the lack of LDA. Knockout mice exhibited no changes in titin isoforms, titin phosphorylation, or other thin filament phosphorylation sites known to affect passive tension or LDA. Mass spectrometry identified several z-disc proteins as myofilament phospho-substrates of GSK-3β. Agreeing with the localization of its targets, GSK-3β that is phosphorylated at Y216 binds to the z-disc. We showed pY216 was necessary and sufficient for z-disc binding using adenoviruses for wild-type, Y216F, and Y216E GSK-3β in neonatal rat ventricular cardiomyocytes. One of GSK-3β's z-disc targets, abLIM-1 (actin-binding LIM protein 1), binds to the z-disc domains of titin that are important for maintaining passive tension. Genetic knockdown of abLIM-1 via siRNA in human engineered heart tissues resulted in enhancement of LDA, indicating abLIM-1 may act as a negative regulator that is modulated by GSK-3β. Last, GSK-3β myofilament localization was reduced in left ventricular myocardium from failing human hearts, which correlated with depressed LDA.ConclusionsWe identified a novel mechanism by which GSK-3β localizes to the myofilament to modulate LDA. Importantly, z-disc GSK-3β levels were reduced in patients with heart failure, indicating z-disc localized GSK-3β is a possible therapeutic target to restore the Frank-Starling mechanism in patients with heart failure
Proteocephalid cestode infection in alien fish, Cichla piquiti Kullander and Ferreira, 2006 (Osteichthyes: Cichlidae), from Volta Grande reservoir, Minas Gerais, Brazil
This work evaluates the variation of the parasitological indexes in 114 Cichla piquiti Kullander and Ferreira, 2006 (tucunaré) infected by two proteocephalid species (Cestoda) for the period of August 1999 to June 2001 in the Volta Grande reservoir, MG, Brazil. The relation between the parasitosis with rainfall and water quality (pH, electric conductivity, oxygen, chlorophyll, transparency and temperature) is discussed. Prevalence of Proteocephalus macrophallus (Diesing, 1850) and/or P. microscopicus (Woodland, 1935) was 83.3%, mean intensity 110.8 and mean abundance 100.7 during the period. A hundred percent prevalence was reported in August and December 1999, April and December 2000 and June 2001. The largest mean intensities of 122.7 (October 1999), 158.8 (December 1999), 96.4 (February 2000), 400.7 (April 2000), 215.6 (October 2000) and 136.4 (December 2000) were observed. Abiotic factors may favour the development of the species of the food chain that sustain the organisms in the diet of "tucunaré", but in this case, there was no correlation (P > 0.05) between the values of prevalence, mean intensity and mean abundance with the rainfall and water quality. At the same time, these organisms may constitute the intermediate hosts of cestodes. The time-course between the fish species development and the parasitosis manifestation in the definitive host can explain the lack of correlation between the parasitological indexes and abiotic factors. The predation on small fishes and cannibalism described for "tucunaré" might explain the high values of prevalence and intensity of infection. The results are also related to the exotic condition of the host in the reservoir