van Opbergen, Chantal J MChantal J Mvan OpbergenNoorman, MaartjeMaartjeNoormanPfenniger, AnnaAnnaPfennigerCopier, Jaël SJaël SCopierVermij, Sarah HelenaSarah HelenaVermij0000-0002-6419-6159Li, ZhenZhenLivan der Nagel, RoelRoelvan der NagelZhang, MingliangMingliangZhangde Bakker, Jacques M TJacques M Tde BakkerGlass, Aaron MAaron MGlassMohler, Peter JPeter JMohlerTaffet, Steven MSteven MTaffetVos, Marc AMarc AVosvan Rijen, Harold V MHarold V Mvan RijenDelmar, MarioMarioDelmarvan Veen, Toon A BToon A Bvan Veen2024-10-282024-10-282019-08-21https://boris-portal.unibe.ch/handle/20.500.12422/185542Human 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.enarrhythmogenic cardiomyopathy calcium handling cardiac pressure overload exercise fibrosis inflammation plakophilin-2 second hit500 - Science::570 - Life sciences; biology600 - Technology::610 - Medicine & healtharticle10.7892/boris.1381713143849410.3390/ijms20174076