Dataset Information

Dynamic adaptation of myocardial proteome during heart failure development after induction of left ventricular pressure overload in mice

ABSTRACT: We analyzed time dependent global proteomic adaptations during heart failure (HF) progression in a mouse model, suffering from left ventricular pressure overload due to transverse aortic constriction (TAC), to gain deeper insights in the disease development and identify new biomarker candidates. The hearts from TAC and sham mice were examined by cardiac MRI on either day 4, 14, 21, 28, 42, and 56 after surgery (n=6 group/time point). At each time point, proteomes of the left (LV) and right ventricles (RV) of TAC and sham mice were analyzed by mass spectrometry (MS).

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart, Cardiac Muscle Tissue Of Ventricle

DISEASE(S): Heart Failure

SUBMITTER: Alexander Benkner

LAB HEAD: Uwe Völker

PROVIDER: PXD007171 | Pride | 2018-07-16

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	120618_OV1_AB__TAC_14d_liV_Pool.pep.xml	Pepxml
	120618_OV1_AB__TAC_14d_liV_Pool.raw	Raw
	120618_OV1_AB__TAC_21d_liV_Pool.pep.xml	Pepxml
	120618_OV1_AB__TAC_21d_liV_Pool.raw	Raw
	120618_OV1_AB__TAC_28d_liV_Pool.pep.xml	Pepxml

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Publications

Dynamic adaptation of myocardial proteome during heart failure development.

Rüdebusch Julia J Benkner Alexander A Poesch Axel A Dörr Marcus M Völker Uwe U Grube Karina K Hammer Elke E Felix Stephan B SB

PloS one 20171003 10

Heart failure (HF) development is characterized by huge structural changes that are crucial for disease progression. Analysis of time dependent global proteomic adaptations during HF progression offers the potential to gain deeper insights in the disease development and identify new biomarker candidates. Therefore, hearts of TAC (transverse aortic constriction) and sham mice were examined by cardiac MRI on either day 4, 14, 21, 28, 42, and 56 after surgery (n = 6 per group/time point). At each t ...[more]

PMID: 28973020

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Project description:Aims: We investigate sex differences and the role of oestrogen receptor beta (ERbeta) in a mouse model of pressure overload-induced myocardial hypertrophy. Methods and results: We performed transverse aortic constriction (TAC) or sham surgery in male and female wild-type (WT) and ER knockout (ERbeta-/-) C57Bl6 mice. All mice were characterised by echocardiography and haemodynamic measurements and were sacrificed nine weeks after surgery. Left ventricular (LV) samples were analysed by microarray profiling, real-time RT-PCR and histology. After nine weeks, WT males showed more hypertrophy and heart failure signs than WT females. Notably, WT females developed a concentric form of hypertrophy, while males developed eccentric hypertrophy. These sex differences were abolished in ERbeta-/- mice. ERbeta deletion augmented the TAC-induced increase in cardiomyocyte diameter in both sexes. Gene expression profiling revealed that male WT hearts had a stronger induction of matrix-related genes and a stronger repression of mitochondrial genes than female hearts. ERbeta-/- mice exhibited a different transcriptome. Induction of pro-apoptotic genes after TAC occurred in ERbeta-/- mice of both sexes with a stronger expression in ERbeta-/- males. Histological analysis revealed, that cardiac fibrosis was more pronounced in male WT TAC than in female mice. This was abolished in ERbeta-/- mice. Apoptosis was significantly induced in both sexes of ERbeta-/- TAC mice, but it was most prominent in males. Conclusion: Female sex offers protection against ventricular chamber dilation in the TAC model. Both the female sex and ER attenuate the development of fibrosis and apoptosis; thus slowing the progression to heart failure. The influence of sex (male/female) and estrogen receptor beta expression (ERbeta knockout/wildtype) on cardiac hypertrophy (transverse aortic constriction/sham operated) was investigated. The left ventricular transcriptome of four individual mice for each combination of the three factors (sex, genotype, surgery) was detected with Affymetrix RAE 430 2.0 GeneChip arrays.

Project description:BACKGROUND: Cardiac hypertrophy compensates for increased biomechanical stress of the heart induced by prevalent cardiovascular pathologies, but can result in cardiac failure if left untreated. We hypothesized that the tail-anchored protein Dysferlin with multiple Ca2+-binding C2-domains is critical for the integrity of the transverse-axial tubule (TAT) network inside cardiomyocytes, and contributes to the proliferation of TAT endomembranes during pressure overload-induced cardiac hypertrophy. OBJECTIVE: To reveal the impact of the membrane fusion and repair protein Dysferlin on TAT network stabilization and proliferation necessary for the hypertrophic growth of cardiomyocytes. METHODS AND RESULTS: Super-resolution light and electron microscopy of mouse cardiomyocytes identified a specific localization of Dysferlin in a vesicular compartment in nanometric proximity to contact sites of the TAT network with the sarcoplasmic reticulum (SR), a.k.a. junctional complexes for Ca2+-induced Ca2+ release. Mass spectrometry was used to characterize the cardiac Dysferlin interactome, thereby identifying a novel protein interaction with the membrane-tethering SR protein Juncophilin-2, a known interactor of L-type Ca2+ channels and Ryanodine Receptor Ca2+ release channels in junctional complexes. While the Dysferlin knockout caused a mild progressive phenotype of dilated cardiomyopathy in the mouse heart, global proteome analysis revealed changes preceding systolic failure. Following transverse aortic constriction (TAC), Dysferlin protein expression was significantly increased in hypertrophied wild-type myocardium, while Dysferlin knockout animals presented markedly reduced left-ventricular hypertrophy. Live-cell membrane imaging demonstrated a profound reorganization of the TAT network in wild-type left-ventricular myocytes post-TAC with robust proliferation of axial tubules, which critically depended on the increased expression of Dysferlin within newly-emerging tubule components. CONCLUSIONS: Dysferlin represents a new molecular target in cardiac disease that protects the integrity of tubule-SR junctional complexes for regulated excitation-contraction coupling, and controls TAT network reorganization and tubular membrane proliferation in cardiomyocyte hypertrophy induced by pressure-overload.