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DCRL Research: Tubulin expression and modification in heart failure with preserved ejection fraction (HFpEF)

Lisa Schulz1, Sarah Werner1, Julia Böttner1, Volker Adams2,3, Philipp Lurz1, Christian Besler1,
Holger Thiele1 & Petra Büttner 1*
Diastolic dysfunction in heart failure with preserved ejection fraction (HFpEF) is characterised by
increased left ventricular stiffness and impaired active relaxation. Underpinning pathomechanisms
are incompletely understood. Cardiac hypertrophy and end stage heart disease are associated with
alterations in the cardiac microtubule (MT) network. Increased amounts and modifications of α-tubulin
associate with myocardial stiffness. MT alterations in HFpEF have not been analysed yet. Using ZSF1
obese rats (O-ZSF1), a validated HFpEF model, we characterised MT-modifying enzymes, quantity
and tyrosination/detyrosination pattern of α-tubulin at 20 and 32 weeks of age. In the left ventricle
of O-ZSF1, α-tubulin concentration (20 weeks: 1.5-fold, p = 0.019; 32 weeks: 1.7-fold, p = 0.042) and
detyrosination levels (20 weeks: 1.4-fold, p = 0.013; 32 weeks: 1.3-fold, p = 0.074) were increased
compared to lean ZSF1 rats. Tyrosination/α-tubulin ratio was lower in O-ZSF1 (20 weeks: 0.8-fold,
p = 0.020; 32 weeks: 0.7-fold, p = 0.052). Expression of α-tubulin modifying enzymes was comparable.
These results reveal new alterations in the left ventricle in HFpEF that are detectable during early
(20 weeks) and late (32 weeks) progression. We suppose that these alterations contribute to diastolic
dysfunction in HFpEF and that reestablishment of MT homeostasis might represent a new target for
pharmacological interventions.
The prevalence of heart failure with preserved ejection fraction (HFpEF) is increasing and nearly every second
patient with heart failure (HF) is diagnosed with HFpEF1,2.
One of the pathophysiological cornerstones of HFpEF
is diastolic dysfunction, characterised by increased myocardial fibrosis, but also increased cellular stiffness3.
well-known pathomechanism of cellular stiffness in HFpEF is altered titin phosphorylation, which directly affects
myocardial contractility4.
Titin regulates the passive elasticity in cardiomyocytes and its hypo-phosphorylation
may lead to increased passive ventricular stiffness. Nevertheless, the complete titin pathomechanism and other
cellular processes responsible for myocardial stiffness are not clarified yet5.
Microtubules (MT) are dynamic, hollow structures and the stiffest filaments in cardiomyocyte cytoskeleton.
They are formed by polymerisation of the heterodimers α-and β-tubulin powered by hydrolysis of GTP6.
especially the α-tubulin subunit are subjected to posttranslational modifications like tyrosination and detyrosination
that regulate restructuring of the cytoskeleton. Tubulin tyrosin ligase (TTL) adds tyrosine to the C-terminus
of free α-tubulin, making it accessible for polymerisation. In contrast, tubulin carboxypeptidase vasohibin 1
(VASH1) removes the tyrosine from α-tubulin, enabling depolymerisation. Thus, tubulin turnover in form of
tyrosination and detyrosination is a cyclic event involving α- tubulin subunits7.
MT tyrosination and detyrosination play an important role in cardiomyocyte contraction8.
A well-balanced
level of detyrosinated MT is important for proper cardiomyocyte contraction as MT bind to sarcomeres and
form a physiological resistance for contraction9.
In patients with hypertrophic and dilated cardiomyopathies
and end stage heart failure higher amount of MT and detyrosinated α-tubulin were described. Further, denser
MT network and high levels of detyrosinated α-tubulin are associated with impaired cardiomyocyte contraction
and increased resistance10.
1Department of Cardiology, Heart Center Leipzig at University of Leipzig, Strümpellstr. 39, 04289 Leipzig,
Germany. 2Department of Cardiology, University Medicine TU Dresden, Dresden, Germany. 3Dresden
Cardiovascular Research Institute and Core Laboratories GmbH, Dresden, Germany. *email: Petra.Buettner@

 as published in Sci Reports.pdf

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