In mice, PKP2 haploinsufficiency combined with exercise induced pro-arrhythmic remodeling, while pressure overload and inflammation exaggerated fibrotic and inflammatory responses compared to wildtype.
Does PKP2 haploinsufficiency modulate the cardiac response to exercise, pressure overload, and inflammation in a murine model?
PKP2 haploinsufficiency in mice exacerbates pro-arrhythmic remodeling in response to exercise and worsens fibrotic and inflammatory responses to pathophysiological stress, providing mechanistic insights into arrhythmogenic cardiomyopathy.
Human variants in plakophilin-2 (PKP2) associate with most cases of familial arrhythmogenic cardiomyopathy (ACM). Recent studies show that PKP2 not only maintains intercellular coupling, but also regulates transcription of genes involved in Ca2+ cycling and cardiac rhythm. ACM penetrance is low and it remains uncertain, which genetic and environmental modifiers are crucial for developing the cardiomyopathy. In this study, heterozygous PKP2 knock-out mice (PKP2-Hz) were used to investigate the influence of exercise, pressure overload, and inflammation on a PKP2-related disease progression. In PKP2-Hz mice, protein levels of Ca2+-handling proteins were reduced compared to wildtype (WT). PKP2-Hz hearts exposed to voluntary exercise training showed right ventricular lateral connexin43 expression, right ventricular conduction slowing, and a higher susceptibility towards arrhythmias. Pressure overload increased levels of fibrosis in PKP2-Hz hearts, without affecting the susceptibility towards arrhythmias. Experimental autoimmune myocarditis caused more severe subepicardial fibrosis, cell death, and inflammatory infiltrates in PKP2-Hz hearts than in WT. To conclude, PKP2 haploinsufficiency in the murine heart modulates the cardiac response to environmental modifiers via different mechanisms. Exercise upon PKP2 deficiency induces a pro-arrhythmic cardiac remodeling, likely based on impaired Ca2+ cycling and electrical conduction, versus structural remodeling. Pathophysiological stimuli mainly exaggerate the fibrotic and inflammatory response.
Opbergen et al. (Wed,) conducted a other in Arrhythmogenic cardiomyopathy. PKP2 haploinsufficiency and environmental modifiers (exercise, pressure overload, inflammation) vs. Wildtype (WT) mice was evaluated on Cardiac response to stress (arrhythmias, fibrosis, inflammation). In mice, PKP2 haploinsufficiency combined with exercise induced pro-arrhythmic remodeling, while pressure overload and inflammation exaggerated fibrotic and inflammatory responses compared to wildtype.
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