Dataset Information

Impact of ultrastructural left-ventricular Ca2+ release unit remodeling in hemodynamic subtypes of severe aortic stenosis

ABSTRACT: Aortic valve stenosis (AS) frequently causes heart disease in elderly patients and is characterized by a broad spectrum of hemodynamic phenotypes, some with life-threatening arrhythmias, and increased risk of death. The guideline for management of severe AS in patients is to improve quality of life by transaortic catheter-based valve replacement (TAVR). However, the mechanisms underlying different AS-associated hemodynamic phenotypes remain poorly understood. Proteome profiling by data-independent acquisition mass spectrometry in individual left-ventricular biopsies quantified 2.273 proteins. 160 showed statistically significant abundance changes in AS hearts compared to non-failing samples. Unbiased hierchical clustering identified four different proteotypes which broadly corresponded to hemodynamic phenotypes. As adult cardiomyocytes undergo distinct stages of subcellular remodeling, we used quantitative superresolution microscopy of candidate proteins in left-ventricular biopsies to determine the consequences of dyadic RyR2 protein changes on AS dysfunction in vivo.

INSTRUMENT(S): TripleTOF 5600

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Heart, Cardiac Muscle Cell

DISEASE(S): Aortic Valve Stenosis

SUBMITTER: Christof Lenz

LAB HEAD: Christof Lenz

PROVIDER: PXD019594 | Pride | 2022-10-17

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	20189424_UP_Reference_HOMSA_wcRAP_wiRT.fasta	Fasta
	20190503_S_BrandenburgIDandQuantitationResults.xlsx	Xlsx
	S_Brandenburg_121218_050419_DIA_A_01.wiff	Wiff
	S_Brandenburg_121218_050419_DIA_A_01.wiff.scan	Wiff
	S_Brandenburg_121218_050419_DIA_A_02.wiff	Wiff

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Publications

Direct proteomic and high-resolution microscopy biopsy analysis identifies distinct ventricular fates in severe aortic stenosis.

Brandenburg Sören S Drews Lena L Schönberger Hanne-Lea HL Jacob Christoph F CF Paulke Nora Josefine NJ Beuthner Bo E BE Topci Rodi R Kohl Tobias T Neuenroth Lisa L Kutschka Ingo I Urlaub Henning H Kück Fabian F Leha Andreas A Friede Tim T Seidler Tim T Jacobshagen Claudius C Toischer Karl K Puls Miriam M Hasenfuß Gerd G Lenz Christof C Lehnart Stephan E SE

Journal of molecular and cellular cardiology 20220906

The incidence of aortic valve stenosis (AS), the most common reason for aortic valve replacement (AVR), increases with population ageing. While untreated AS is associated with high mortality, different hemodynamic subtypes range from normal left-ventricular function to severe heart failure. However, the molecular nature underlying four different AS subclasses, suggesting vastly different myocardial fates, is unknown. Here, we used direct proteomic analysis of small left-ventricular biopsies to i ...[more]

PMID: 36084744

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Project description:Multiple molecular and cellular mechanisms are associated with the initiation and progression of aortic valve disease. Alterations in ECM remodeling, increased expression of pro-inflammatory cytokines, calcification, lipid deposition and changes in valve cell phenotype have demonstrated roles in development of aortic valve disease. Mechanical stimulation has a significant role in determining the physiological properties of valve tissue and an altered hemodynamic environment may result in pathological changes. We used microarrays to detail the global of gene expression profiles underlying valve remodeling during valve exposure to of two levels of cyclic mechanical pressure (normotensive 0-80mmHg and hypertensive 0-120mmHg ) on porcine valve tissue transcriptome using Sus Scrofa cDNA microarrays from Affymetrix and we identified distinct classes of up-regulated genes during this process. Hybridizations were carried out with RNA isolated from six independetn samples of valve tissue exposed to normotensive and hypertensive pressure for 24 hours at 1hz frecuency. Differentially expressed genes were identified by The t test with the option of unequal variance was used to calculate P values for each gene. The fold change and Q values for each gene were calculated with SAM program with permutation of 500 . Biological modeling of the differentially expressed genes (DE) was carried out based on GO groups and network analysis in ingenuity Pathway Analysis (IPA). Experiment Overall Design: The experimental design included three biological samples of porcine valve leaflets exposed to cyclic pressures of 0-80 or 0-120 mmHg for 24 hours, representing normotensive and hypertensive diastolic transvalvular pressure, respectively. Using Affymetrix porcine microarrays, we compared global gene expression profiles of aortic valve leaflets exposed to elevated and normal physiological pressure conditions . The effects of cyclic pressure on the transcriptome was determined by comparing the quantity and magnitud of change in gene expression levels of valve leflets, as well evaluating the molecular function each gene has in the cell,in the presence of hypertennsive (experimental) and normotensve pressurec (control).