Plakophilin-2 Haploinsufficiency Causes Calcium Handling Deficits and Modulates the Cardiac Response Towards Stress.
Chantal J M van OpbergenMaartje NoormanAnna PfennigerJaël S CopierSarah H VermijZhen LiRoel van der NagelMingliang ZhangJacques M T de BakkerAaron M GlassPeter J MohlerSteven M TaffetMarc A VosHarold V M van RijenMario DelmarToon A B van VeenPublished in: International journal of molecular sciences (2019)
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.
Keyphrases
- cell death
- inflammatory response
- high intensity
- left ventricular
- heart failure
- oxidative stress
- physical activity
- type diabetes
- poor prognosis
- high fat diet induced
- traumatic brain injury
- atrial fibrillation
- small molecule
- gene expression
- genome wide
- body composition
- metabolic syndrome
- lipopolysaccharide induced
- cell proliferation
- congenital heart disease
- protein protein
- smoking cessation
- replacement therapy