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Identification of PITX2 as a novel factor in arrhythmogenic cardiomyopathy pathogenesis

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE208214 | GEO | 2023/03/02

REPOSITORIES: GEO

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Identification of PITX2 as a novel factor in arrhythmogenic cardiomyopathy pathogenesis [KI]

Project description:In this study, we identified a novel heterozygous variant within DSP (c.3562T>C) in a patient diagnosed with ACM. Using CRISPR/Cas9 we corrected patient-derived human induced pluripotent stem cells (hiPSC) and created a knock-in (KI) hiPSC line with the same mutation. Compared to wildtype cardiomyocytes, we observed a prolonged action potential duration (APD) and reduced expression of desmosomal components, which was paralleled by abnormal levels of essential cardiac ion channels. Strikingly, the transcription factor paired-like homeodomain 2 (PITX2), which acts as a repressor of ion channel-related genes, was induced in these cells. Together, we identified PITX2 as a potential missing link between mutations in DSP and the cardiac conductance abnormalities often seen in these patients.

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Identification of PITX2 as a novel factor in arrhythmogenic cardiomyopathy pathogenesis [patient line]

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Identification of PITX2 as a novel factor in arrhythmogenic cardiomyopathy pathogenesis

Project description:Identification of PITX2 as a novel factor in arrhythmogenic cardiomyopathy pathogenesis

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Novel heart specific long non-coding RNAs contribute to pathogenesis of Arrhythmogenic Cardiomyopathy

Project description:This SuperSeries is composed of the SubSeries listed below.

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Identification of PITX2 as a novel factor in arrhythmogenic cardiomyopathy pathogenesis [KI]

Project description:Identification of PITX2 as a novel factor in arrhythmogenic cardiomyopathy pathogenesis [KI]

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Identification of PITX2 as a novel factor in arrhythmogenic cardiomyopathy pathogenesis [patient line]

Project description:Identification of PITX2 as a novel factor in arrhythmogenic cardiomyopathy pathogenesis [patient line]

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Genome-wide profiling of the cardiac transcriptome identifies novel heart specific long non-coding RNAs involved in pathogenesis of Arrhythmogenic Cardiomyopathy

Project description:This SuperSeries is composed of the SubSeries listed below.

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PITX2 induction leads to impaired cardiomyocyte function in arrhythmogenic cardiomyopathy.

Project description:Arrhythmogenic cardiomyopathy (ACM) is an inherited progressive disease characterized by electrophysiological and structural remodeling of the ventricles. However, the disease-causing molecular pathways, as a consequence of desmosomal mutations, are poorly understood. Here, we identified a novel missense mutation within desmoplakin in a patient clinically diagnosed with ACM. Using CRISPR-Cas9, we corrected this mutation in patient-derived human induced pluripotent stem cells (hiPSCs) and generated an independent knockin hiPSC line carrying the same mutation. Mutant cardiomyocytes displayed a decline in connexin 43, NaV1.5, and desmosomal proteins, which was accompanied by a prolonged action potential duration. Interestingly, paired-like homeodomain 2 (PITX2), a transcription factor that acts a repressor of connexin 43, NaV1.5, and desmoplakin, was induced in mutant cardiomyocytes. We validated these results in control cardiomyocytes in which PITX2 was either depleted or overexpressed. Importantly, knockdown of PITX2 in patient-derived cardiomyocytes is sufficient to restore the levels of desmoplakin, connexin 43, and NaV1.5.

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Inflammation shapes pathogenesis of murine arrhythmogenic cardiomyopathy.

Project description:Arrhythmogenic cardiomyopathy (AC) is an incurable genetic disease, whose pathogenesis is poorly understood. AC is characterized by arrhythmia, fibrosis, and cardiodilation that may lead to sudden cardiac death or heart failure. To elucidate AC pathogenesis and to design possible treatment strategies of AC, multiple murine models have been established. Among them, mice carrying desmoglein 2 mutations are particularly valuable given the identification of desmoglein 2 mutations in human AC and the detection of desmoglein 2 auto-antibodies in AC patients. Using two mouse strains producing either a mutant desmoglein 2 or lacking desmoglein 2 in cardiomyocytes, we test the hypothesis that inflammation is a major component of disease pathogenesis. We show that multifocal cardiomyocyte necrosis initiates a neutrophil-dominated inflammatory response, which also involves macrophages and T cells. Increased expression of Ccl2/Ccr2, Ccl3/Ccr5, and Cxcl5/Cxcr2 mRNA reflects the observed immune cell recruitment. During the ensuing acute disease phase, Mmp12+ and Spp1+ macrophages and T cells accumulate in scars, which mature from cell- to collagen-rich. The expression of Cx3cl1/Cx3cr1, Ccl2/Ccr2, and Cxcl10/Cxcr3 dominates this disease phase. We furthermore find that during chronic disease progression macrophages and T cells persist within mature scars and are present in expanding interstitial fibrosis. Ccl12 and Cx3cl1 are predominant chemokines in this disease phase. Together, our observations provide strong evidence that specific immune cell populations and chemokine expression profiles modulate inflammatory and repair processes throughout AC progression.

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