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The tubulin code during cardiac hypertrophy and failure [III]

ABSTRACT: A proliferated and post-translationally modified microtubule network underlies cellular growth in cardiac hypertrophy and contributes to contractile dysfunction in heart failure. Yet how the heart achieves this modified network is poorly understood. Determining how the “tubulin code” – the permutations of tubulin isoforms and post-translational modifications - is rewritten upon cardiac stress may provide new targets to modulate cardiac remodeling. Further, while tubulin can autoregulate its own expression, it is unknown if autoregulation is operant in the heart or tuned in response to stress. Here we use heart failure patient samples and murine models of cardiac remodeling to interrogate transcriptional, autoregulatory, and post-translational mechanisms that contribute to microtubule network remodeling at different stages of heart disease. We find that autoregulation is operant across tubulin isoforms in the heart and leads to an apparent disconnect in tubulin mRNA and protein levels in heart failure. We also find that within 4 hours of a hypertrophic stimulus and prior to cardiac growth, microtubule detyrosination is rapidly induced to help stabilize the network. This occurs concomitant with rapid transcriptional and autoregulatory activation of specific tubulin isoforms and microtubule motors. Upon continued hypertrophic stimulation, there is an increase in post-translationally modified microtubule tracks and anterograde motors to support cardiac growth, while total tubulin content increases through progressive transcriptional and autoregulatory induction of tubulin isoforms. Our work provides a new model for how the tubulin code is rapidly rewritten to establish a proliferated, stable microtubule network that drives cardiac remodeling, and provides the first evidence of tunable tubulin autoregulation during pathological progression.

ORGANISM(S): Mus musculus

PROVIDER: GSE194393 | GEO | 2022/01/28

REPOSITORIES: GEO

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Project description:In this project, effects of chronic temperature changes on the transcriptome of the rainbow trout heart (Oncorhynchus mykiss) were examined. Ectothermic animals of north-temperate latitudes experience large seasonal changes in temperature which strongly affect the rate of body functions. To compensate for the effects of temperature changes ectotherms can respond to chronic temperature changes by increasing the quantity of tissue or enzyme needed for different physiological tasks, or by expressing proteins isoforms which are more appropriate for the new thermal conditions. On the other hand, proteins which are needed in lesser amounts in the new thermal regime could be depressed or down-regulated. Although expression of proteins can be changed by multiple mechanisms during synthesis and degradation, temperature dependent changes in transcription of genes is probably the most important factor in modifying the proteome of the tissues. Rainbow trout are active throughout their thermal tolerance range (0-25Â°C). Maintenance of adequate cardiac function at different thermal conditions requires a thorough change of the cardiac phenotype which appears as compensatory changes in relative heart mass, energy metabolism, nervous and humoral control of cardiac contractility and in electrical and mechanical properties of the trout heart. Such an extensive structural and functional remodeling of the heart probably necessitates both qualitative and quantitative changes among the numerous macromolecules which constitute the cardiac phenotype and cannot, therefore, be solely based on posttranslational modification of proteins but is expected to require differential gene expression. As a power supply of the circulatory system, the heart is in the focal point of physiological plasticity and sets limits for the activity level of the animal in different thermal conditions. Although several aspects of heart function have been studied in thermally acclimated fish and a number of structural changes have been noticed on exposure to different temperatures, the cellular and molecular mechanisms involved in chronic thermal stress of the fish heart are only partially elucidated. An interesting and poorly examined feature of the cold-acclimated phenotype of the trout heart is the increased heart mass which attenuates the depressive effect of low temperature on cardiac pump function. The heart is a complex organ composed of multiple tissues which together provide the system all necessary qualifications for cardiac pump function. In addition to the contractile and metabolic machinery of the cardiac myocytes, the amount and quality of the extracellular matrix also contribute to the properties of the heart as a muscular pump. Due to the complexity of the heart an enormous amounts of research efforts are needed to find out and examine all crucial aspects of cardiac plasticity required for thermal acclimation. In this regard the screening of gene expression by cDNA micro arrays might provide a broader view to genomic basis of cardiac remodeling under changing temperatures and aid to reveal the candidate genes which are important for thermal acclimation and which might remain unnoticed by traditional biochemical and physiological methods. In the present study we the steady-state effects of temperature acclimation on gene expression of the rainbow trout heart were screened by micro array analysis.

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The tubulin code during cardiac hypertrophy and failure [III]

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