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Innate immune activation modulates contractile and electrical dysfunction in engineered heart tissue models fordesmoplakin(DSP)cardiomyopathy.

ABSTRACT: Innate immune activation modulates contractile and electrical dysfunction in engineered heart tissue models fordesmoplakin(DSP)cardiomyopathy.

PROVIDER: PRJNA1041887 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26866808_1.fastq.gz	Fastqsanger.gz
	SRR26866808_2.fastq.gz	Fastqsanger.gz
	SRR26866809_1.fastq.gz	Fastqsanger.gz
	SRR26866809_2.fastq.gz	Fastqsanger.gz
	SRR26866810_1.fastq.gz	Fastqsanger.gz

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Innate immune activation modulates contractile and electrical dysfunction in engineered heart tissue models fordesmoplakin(DSP)cardiomyopathy.

Project description:Desmosomes are specialized cell-cell junctions critically important in the heart, where their disruption promotes arrhythmogenic cardiomyopathy (ACM). Individuals carrying truncating variants in the desmosomal gene desmoplakin (DSP) often show a prominent inflammatory component in the absence of known antigenic stimuli, termed “hot phase” arrythmia. To assess the role of innate immune activation in DSP-cardiomyopathy, we generated engineered heart tissues (EHTs) from two patients with heterozygous DSP truncation variants (DSPtv, p.E1597X and p.R1951X). We also generated EHTs with homozygous DSP deletion (DSP-/-) for modeling. DSP-/- EHTs revealed impaired force production and reduced conduction velocity compared to isogenic controls, features consistent with ACM. RNA sequencing and protein characterization demonstrated a dramatic increase in innate immune activation in DSP-/- EHTs. Similarly, patient-derived DSPtv EHTs show enhanced sensitivity to inflammatory stimuli seen as reduced contractility and greater cytokine release. Inhibition of NFκB signaling improved baseline force production and mechanical response to strain in DSPtv EHTs, indicating that anti-inflammatory modulation may improve mechanical function in DSP deficient hearts. Furthermore, genomic correction of p.R1951X using adenine base editing reduced inflammatory biomarkers in cultured EHTs. Taken together, these data identify that DSPtv promote innate immune activation, creating an arrhythmogenic substrate in the concealed phase of ACM.

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