Dataset Information

Extracellular Matrix Proteomics of Human Heart Failure.

ABSTRACT: MS analysis of human cardiac samples from left ventricles of patients undergoing cardiac transplantation due to ischaemic heart failure. Analysis of extracellular matrix enriched extracts.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Heart

DISEASE(S): Myocardial Ischemia

SUBMITTER: Javier Barallobre-Barreiro

LAB HEAD: Javier Barallobre-Barreiro

PROVIDER: PXD024135 | Pride | 2021-12-15

REPOSITORIES: Pride

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Publications

Extracellular Matrix in Heart Failure: Role of ADAMTS5 in Proteoglycan Remodeling.

Barallobre-Barreiro Javier J Radovits Tamás T Fava Marika M Mayr Ursula U Lin Wen-Yu WY Ermolaeva Elizaveta E Martínez-López Diego D Lindberg Eric L EL Duregotti Elisa E Daróczi László L Hasman Maria M Schmidt Lukas E LE Singh Bhawana B Lu Ruifang R Baig Ferheen F Siedlar Aleksandra Malgorzata AM Cuello Friederike F Catibog Norman N Theofilatos Konstantinos K Shah Ajay M AM Crespo-Leiro Maria G MG Doménech Nieves N Hübner Norbert N Merkely Béla B Mayr Manuel M

Circulation 20211122 25

<h4>Background</h4>Remodeling of the extracellular matrix (ECM) is a hallmark of heart failure (HF). Our previous analysis of the secretome of murine cardiac fibroblasts returned ADAMTS5 (a disintegrin and metalloproteinase with thrombospondin motifs 5) as one of the most abundant proteases. ADAMTS5 cleaves chondroitin sulfate proteoglycans such as versican. The contribution of ADAMTS5 and its substrate versican to HF is unknown.<h4>Methods</h4>Versican remodeling was assessed in mice lacking th ...[more]

PMID: 34806902

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Project description:Aims: A mutation in the phospholamban (PLN) gene, leading to deletion of Arg14 (R14del), has been associated with malignant arrhythmias and ventricular dilation. Identifying pre-symptomatic carriers with vulnerable myocardium is crucial because arrhythmia can result in sudden cardiac death, especially in young adults with PLN-R14del mutation. This study aimed at assessing the efficiency and efficacy of in vivo genome editing, using CRISPR/Cas9 and a cardiotropic adeno-associated virus (AAV9), in improving cardiac function in young adult mice expressing the human PLN-R14del. Methods and Results: Humanized mice were generated expressing human wild-type (hPLN-WT) or mutant (hPLN-R14del) PLN in the heterozygous state, mimicking human carriers. Cardiac magnetic resonance imaging at 12 weeks of age showed bi-ventricular dilation and increased stroke volume in mutant vs. WT mice, with no deficit in ejection fraction or cardiac output. Challenge of ex vivo hearts with isoproterenol and rapid pacing unmasked higher propensity for sustained ventricular tachycardia (VT) in hPLN-R14del relative to hPLN-WT. Specifically, the VT threshold was significantly reduced (20.3±1.2 Hz in hPLN-R14del vs. 25.7±1.3 Hz in WT, p<0.01) reflecting higher arrhythmia burden. To inactivate the R14del allele, mice were tail-vein-injected with AAV9.CRISPR/Cas9/gRNA or AAV9 empty capsid (controls). CRISPR-Cas9 efficiency was evaluated by droplet digital PCR and NGS-based amplicon sequencing. In vivo gene editing significantly reduced end diastolic and stroke volumes in hPLN-R14del CRISPR-treated mice compared to controls. Susceptibility to VT was also reduced, as the VT threshold was significantly increased relative to controls (30.9±2.3 Hz vs. 21.3±1.5 Hz; p<0.01). Conclusions: This study is the first to show that disruption of hPLN-R14del allele by AAV9- CRISPR/Cas9 improves cardiac function and reduces VT susceptibility in humanized PLN-R14del mice, offering preclinical evidence for translatable approaches to therapeutically suppress the arrhythmogenic phenotype in human patients with PLN-R14del disease.

Dataset Information

Extracellular Matrix Proteomics of Human Heart Failure.

Publications

Extracellular Matrix in Heart Failure: Role of ADAMTS5 in Proteoglycan Remodeling.

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