To explore the downstream genes of PKP2
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA655489 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12395846.fastq.gz | Fastqsanger.gz | |||
| SRR12395847.fastq.gz | Fastqsanger.gz |
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Project description:Introduction: Arrhythmogenic Cardiomyopathy (AC) is an inherited disease that is caused by desmosome protein mutation with plakophilin 2 (PKP2) mutation being most common. AC is known to cause sporadic ventricular arrhythmias, myocyte damage, and subepicardial fibrosis. Given the origin of fibrosis from epicardium, we wanted to understand how epicardium-derived cells (EDCs) contribute to the AC pathogenesis. Hypothesis: EDCs propagate the pro-inflammatory signaling that contributes to AC pathogenesis. Methods: We developed transgenic mice that lack PKP2 in cardiomyocytes (PKP2-cKO) or in both cardiomyocyte and epicardial cells (PKP2-ceKO) via the tissue-specific expression of tamoxifen-inducible Cre recombinase. Tamoxifen injected mice expressing Cre in cardiomyocytes, but with no floxed PKP2 gene, was used as a control. EDCs were traced with Cre-dependent Green Fluorescence Protein (GFP). Non-myocyte populations were isolated 21 days post-tamoxifen injection for single cell RNA-sequencing (scRNA-seq) using 10X Genomics platform. Perfused hearts were separated into left and right ventricle for qRT-PCR. Immunohistochemistry was used for cardiac structure and cellular composition. Echocardiography was performed to measure cardiac physiology. Results: The scRNA-seq analysis identified an epicardium-derived fibroblast population that secretes pro-inflammatory cytokines, including CCL2, CCL7, Thbs1, and PTX3. While pro-inflammatory EDCs are found in both PKP2-cKO and PKP2-ceKO mice, they were most numerous in PKP2-ceKO mice. Importantly, macrophages and B cells accumulated in both PKP2-cKO and PKP2-ceKO mice compared to controls. qRT-PCR confirmed that the expression of genes encoding fibrosis markers (POSTN, Col1A1, Col1A2, and Col3A1), pro-inflammatory fibroblast markers (CCL2, CCL7, Thbs1, PTX3), macrophage markers (F4/80, Cx3cr1, Spp1, Trem2, and CCR2), and B cell markers (CD19 and CD79b) were significantly enriched in both PKP2-cKO and PKP2-ceKO mice compared to control. Our expression and histologic data also revealed an exaggerated pro-inflammatory response in PKP2-ceKO mice, that progresses from the right to bi-ventricular predominance. However, echocardiography showed no significant difference in cardiac function between PKP2-cKO and PKP2-ceKO, and B cell depletion did not alter disease progression. Conclusion: A subset of epicardium-derived fibroblasts in PKP2 KO mice secretes pro-inflammatory cytokines that contributes to cardiomyocyte damage and cardiac fibrosis in AC.
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Project description:Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial cardiac disease associated with ventricular arrhythmias and an increased risk of sudden cardiac death. Currently, there are no approved treatments that address the underlying genetic cause of this disease, representing a significant unmet need. Mutations in Plakophilin-2 (PKP2), encoding a desmosomal protein, account for approximately 40% of ARVC cases and result in reduced gene expression. Methods: Our goal is to examine the feasibility and the efficacy of adeno-associated virus 9 (AAV9)-mediated restoration of PKP2 expression in a cardiac specific knock-out mouse model of Pkp2. Results: We show that a single dose of AAV9:PKP2 gene delivery prevents disease development before the onset of cardiomyopathy and attenuates disease progression after overt cardiomyopathy. Restoration of PKP2 expression leads to a significant extension of lifespan by restoring cellular structures of desmosomes and gap junctions, preventing or halting decline in left ventricular ejection fraction, preventing or reversing dilation of the right ventricle, ameliorating ventricular arrhythmia event frequency and severity, and preventing adverse fibrotic remodeling. RNA sequencing analyses show that restoration of PKP2 expression leads to highly coordinated and durable correction of PKP2-associated transcriptional networks beyond desmosomes, revealing a broad spectrum of biological perturbances behind ARVC disease etiology. Conclusions: We identify fundamental mechanisms of PKP2-associated ARVC beyond disruption of desmosome function. The observed PKP2 dose-function relationship indicates that cardiac-selective AAV9:PKP2 gene therapy may be a promising therapeutic approach to treat ARVC patients with PKP2 mutations.
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Project description:Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial cardiac disease associated with ventricular arrhythmias and an increased risk of sudden cardiac death. Currently, there are no approved treatments that address the underlying genetic cause of this disease, representing a significant unmet need. Mutations in Plakophilin-2 (PKP2), encoding a desmosomal protein, account for approximately 40% of ARVC cases and result in reduced gene expression. Methods: Our goal is to examine the feasibility and the efficacy of adeno-associated virus 9 (AAV9)-mediated restoration of PKP2 expression in a cardiac specific knock-out mouse model of Pkp2. Results: We show that a single dose of AAV9:PKP2 gene delivery prevents disease development before the onset of cardiomyopathy and attenuates disease progression after overt cardiomyopathy. Restoration of PKP2 expression leads to a significant extension of lifespan by restoring cellular structures of desmosomes and gap junctions, preventing or halting decline in left ventricular ejection fraction, preventing or reversing dilation of the right ventricle, ameliorating ventricular arrhythmia event frequency and severity, and preventing adverse fibrotic remodeling. RNA sequencing analyses show that restoration of PKP2 expression leads to highly coordinated and durable correction of PKP2-associated transcriptional networks beyond desmosomes, revealing a broad spectrum of biological perturbances behind ARVC disease etiology. Conclusions: We identify fundamental mechanisms of PKP2-associated ARVC beyond disruption of desmosome function. The observed PKP2 dose-function relationship indicates that cardiac-selective AAV9:PKP2 gene therapy may be a promising therapeutic approach to treat ARVC patients with PKP2 mutations.
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