Key result
PKP2 deficiency in cardiac myocytes upregulated transcripts in inflammatory and immune response pathways, inversely correlating with PKP2 abundance in human transcriptomes.
Why the study?
PKP2 mutations associate with ARVC, where inflammation plays a key role, but whether PKP2 transcript abundance is endogenously linked to inflammatory and immune pathways in adult cardiac myocytes was unknown.
PKP2 deficiency in cardiac myocytes intrinsically upregulates inflammatory and immune response genes, suggesting targeted anti-inflammatory therapy may be effective in ARVC.
May implicate immune activation in PKP2 cardiomyopathy; hypothesis-generating and requires prospective validation before clinical consideration.
Plakophilin-2 (PKP2) is classically defined as a component of the desmosome. Besides its role in cell–cell adhesion, PKP2 can modulate transcription through intracellular signals initiated at the site of cell–cell contact. Mutations in PKP2 associate with arrhythmogenic right ventricular cardiomyopathy (ARVC). Recent data demonstrate that inflammation plays a key role in disease progression; other results show an abundance of anti-heart antibodies in patients with confirmed diagnosis of ARVC. Here, we test the hypothesis that, in adult cardiac myocytes, PKP2 transcript abundance is endogenously linked to the abundance of transcripts participating in the inflammatory/immune response. Cardiac-specific, tamoxifen (TAM)-activated PKP2-knockout mice (PKP2cKO) were crossed with a RiboTag line to allow characterization of the ribosome-resident transcriptome of cardiomyocytes after PKP2 knockdown. Data were combined with informatics analysis of human cardiac transcriptome using GTEx. Separately, the presence of non-myocyte cells at the time of analysis was assessed by imaging methods. We identified a large number of transcripts upregulated consequent to PKP2 deficiency in myocytes, inversely correlated with PKP2 abundance in human transcriptomes, and part of functional pathways associated with inflammatory/immune responses. Our data support the concept that PKP2 is transcriptionally linked, in cardiac myocytes, to genes coding for host-response molecules even in the absence of exogenous triggers. Targeted anti-inflammatory therapy may be effective in ARVC.
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Pérez-Hernández et al. (2021) studied Arrhythmogenic right ventricular cardiomyopathy (ARVC). PKP2 deficiency vs. Normal PKP2 abundance was evaluated on Transcript abundance of inflammatory/immune response genes. PKP2 deficiency in cardiac myocytes upregulated transcripts in inflammatory and immune response pathways, inversely correlating with PKP2 abundance in human transcriptomes.
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