Biology subjects

Asimaki, A.

Publications and source records attributed to Asimaki, A..

3 recordsLinked to original sources

bioRxiv2024

Interleukin-1β Drives Disease Progression in Arrhythmogenic Cardiomyopathy

Arrhythmogenic cardiomyopathy (ACM) is a genetic form of heart failure that affects 1 in 5000 people globally and is caused by mutations in cardiac desmosomal proteins including PKP2, DSP, and DSG2. Individuals with ACM suffer from ventricular arrhythmias, sudden cardiac death, and heart failure. There are few effective treatments and heart transplantation remains the best option for many affected individuals. Here we performed single nucleus RNA sequencing (snRNAseq) and spatial transcriptomics on myocardial samples from patients with ACM and control donors. We identified disease-associated spatial niches characterized by co-existence of fibrotic and inflammatory cell types and failing cardiac myocytes. The inflammatory-fibrotic niche co-localized to areas of cardiac myocyte loss and was comprised of FAP (fibroblast activation protein) and POSTN (periostin) expressing fibroblasts and macrophages expressing NLRP3 (NLR family pyrin domain containing 3) and NFB activated genes. Using homozygous Desmoglein-2 mutant (Dsg2mut/mut) mice, we identified analogous populations of Postn expressing fibroblasts and inflammatory macrophage populations that co-localized within diseased areas. Detailed single cell RNA sequencing analysis of inflammatory macrophage subsets that were increased in ACM samples revealed high levels of interleukin-1{beta} (Il1b) expression. To delineate the possible benefit of targeting IL-1{beta} in ACM, we treated Dsg2mut/mut mice with an anti-IL-1{beta} neutralizing antibody and observed attenuated fibrosis, reduced levels of inflammatory cytokines and chemokines, preserved cardiac function, and diminished conduction slowing and automaticity, key mechanisms of arrhythmogenesis. These results suggest that currently approved therapeutics that target IL-1{beta} or IL-1 signaling may improve outcomes for patients with ACM.

immunology↗

bioRxiv2024

Inhibition of Soluble Epoxide Hydrolase Reduces Inflammation and Myocardial Injury in Arrhythmogenic Cardiomyopathy

Previous studies have implicated persistent innate immune signaling in the pathogenesis of arrhythmogenic cardiomyopathy (ACM), a familial non-ischemic heart muscle disease characterized by life-threatening arrhythmias and progressive myocardial injury. Here, we provide new evidence implicating inflammatory lipid autocoids in ACM. We show that specialized pro-resolving lipid mediators are reduced in hearts of Dsg2mut/mut mice, a well characterized mouse model of ACM. We also found that ACM disease features can be reversed in rat ventricular myocytes expressing mutant JUP by the pro-resolving epoxy fatty acid (EpFA) 14,15-eicosatrienoic acid (14-15-EET), whereas 14,15-EE-5(Z)E which antagonizes actions of the putative 14,15-EET receptor, intensified nuclear accumulation of the desmosomal protein plakoglobin. Soluble epoxide hydrolase (sEH), an enzyme that rapidly converts pro-resolving EpFAs into polar, far less active or even pro-inflammatory diols, is highly expressed in cardiac myocytes in Dsg2mut/mut mice. Inhibition of sEH prevented progression of myocardial injury in Dsg2mut/mut mice and led to recovery of contractile function. This was associated with reduced myocardial expression of genes involved in the innate immune response and fewer pro- inflammatory macrophages expressing CCR2, which mediate myocardial injury in Dsg2mut/mut mice. These results suggest that pro-inflammatory eicosanoids contribute to the pathogenesis of ACM and, further, that inhibition of sEH may be an effective, mechanism-based therapy for ACM patients.

cell biology↗

bioRxiv2023

Innate Immune Signaling in Hearts and Buccal Mucosa Cells of Patients with Arrhythmogenic Cardiomyopathy

STRUCTURED ABSTRACTO_ST_ABSObjectivesC_ST_ABSWe sought to determine if persistent innate immune signaling via NF{kappa}B occurs in cardiac myocytes in patients with arrhythmogenic cardiomyopathy and if this is associated with myocardial infiltration of pro-inflammatory cells expressing CCR2. We also determined if buccal mucosa cells from young subjects with inherited disease alleles exhibit NF{kappa}B signaling. BackgroundNF{kappa}B signaling in cardiac myocytes causes disease in a mouse model of arrhythmogenic cardiomyopathy by mobilizing CCR2-expressing macrophages which promote myocardial injury and arrhythmias. Buccal mucosa cells exhibit pathologic features similar to those seen in cardiac myocytes in patients with arrhythmogenic cardiomyopathy. MethodsWe analyzed myocardium from arrhythmogenic cardiomyopathy patients who died suddenly or required cardiac transplantation. We also analyzed buccal mucosa cells from young subjects with inherited disease alleles. The presence of immunoreactive signal for RelA/p65 in nuclei of cardiac myocytes and buccal cells was used as a reliable indicator of active NF{kappa}B signaling. We also counted myocardial CCR2-expressing cells. ResultsNF{kappa}B signaling was seen in cardiac myocytes in 34 of 36 cases of arrhythmogenic cardiomyopathy but in none of 19 age-matched controls. Cells expressing CCR2 were increased in patient hearts in numbers directly correlated with the number of cardiac myocytes showing NF{kappa}B signaling. NF{kappa}B signaling also occurred in buccal cells in young subjects with active disease. ConclusionsPatients with clinically active arrhythmogenic cardiomyopathy exhibit persistent innate immune responses in cardiac myocytes and buccal mucosa cells reflecting an inflammatory process that fails to resolve. Such individuals may benefit from anti-inflammatory therapy. CONDENSED ABSTRACTNF{kappa}B signaling in cardiac myocytes causes arrhythmias and myocardial injury in a mouse model of arrhythmogenic cardiomyopathy by mobilizing pro-inflammatory CCR2-expressing macrophages to the heart. Based on these new mechanistic insights, we analyzed hearts of arrhythmogenic cardiomyopathy patients who died suddenly or required cardiac transplantation. We observed active NF{kappa}B signaling in cardiac myocytes associated with marked infiltration of CCR2-expressing cells. We also observed NF{kappa}B signaling in buccal mucosa cells obtained from young subjects with active disease. Thus, anti-inflammatory therapy may be effective in arrhythmogenic cardiomyopathy. Screening buccal cells may be a reliable way to identify patients most likely to benefit. HIGHLIGHTS- Inflammation likely contributes to the pathogenesis of arrhythmogenic cardiomyopathy but the responsible mechanisms and the roles of specific classes of immune cells remain undefined. - NF{kappa}B signaling in cardiac myocytes is sufficient to cause disease in a mouse model of arrhythmogenic cardiomyopathy by mobilizing injurious myeloid cells expressing CCR2 to the heart. - Here, we provide evidence of persistent NF{kappa}B signaling in cardiac myocytes and increased CCR2-expressing cells in hearts of patients with arrhythmogenic cardiomyopathy. We observed a close correlation between the number of cardiac myocytes with active NF{kappa}B signaling and the number of CCR2-expressing cells in patient hearts. - We also provide evidence of active NF{kappa}B signaling in buccal mucosa cells associated with initial onset of disease and/or disease progression in young subjects with arrhythmogenic cardiomyopathy alleles.

pathology↗