Early cardiac inflammation as a driver of murine model of Arrhythmogenic Cardiomyopathy

Abstract

The study of a desmoglein 2 murine model of arrhythmogenic cardiomyopathy revealed cardiac inflammation as a key early event leading to fibrosis. Arrhythmogenic Cardiomyopathy (AC) is an inherited heart muscle disorder leading to ventricular arrhythmias and heart failure due to abnormalities in the cardiac desmosome. We examined how loss of desmoglein 2 (Dsg2) in the young murine heart leads to development of AC. Cardiomyocyte apoptosis was an early cellular phenotype and RNA-Seq analysis revealed early activation of inflammatory-associated pathways in Dsg2 null (Dsg2−/−) hearts at postnatal day 14 (Two weeks) that were absent in the fibrotic heart of adult mice (Ten weeks). This included upregulation of iRhom2/ADAM17 and its associated pro-inflammatory cytokines and receptors such as TNFα, IL6R and IL-6. Furthermore, genes linked to specific macrophage populations were upregulated. This suggests cardiomyocyte stress triggers an early immune response to clear apoptotic cells allowing tissue remodelling later on in the fibrotic heart. Our analysis at different disease stages implicate inflammation related to loss of desmoglein 2 as a major mechanism for disease progression.

Cardiomyocyte cohesion is increased after ADAM17 inhibition

“…A recent study in keratinocytes also revealed that ADAM17 inhibition did not alter EGFR signaling (Kugelmann et al, 2022). In mice lacking DSG2, ADAM17 was increased in 2 week old hearts (Ng et al, 2021). Furthermore, increased levels of EGF, indicating an increased EGFR activity, also increased the protein levels of ADAM17 (Santiago-Josefat et al, 2007).…”

“…A deficiency of tissue inhibitor of metalloproteases 3 (TIMP3), a physiological inhibitor of ADAM17, can result in DCM (Fedak et al, 2004). Finally, in a Dsg2 −/− murine model for arrhythmogenic cardiomyopathy (AC), ADAM17 levels were increased in the hearts of 2 week old mice (Ng et al, 2021).…”