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Loss of Nuclear Envelope Integrity and Increased Oxidant Production Cause DNA Damage in Adult Hearts Deficient in PKP2:A Molecular Substrate of ARVC
- Source :
- Perez-Hernandez , M , van Opbergen , C J M , Bagwan , N , Vissing , C R , Marron-Linares , G M , Zhang , M , Vega , E T , Sorrentino , A , Drici , L , Sulek , K , Zhai , R , Hansen , F B , Christensen , A H , Boesgaard , S , Gustafsson , F , Rossing , K , Small , E M , Davies , M J , Rothenberg , E , Sato , P Y , Cerrone , M , Jensen , T H L , Qvortrup , K , Bundgaard , H , Delmar , M & Lundby , A 2022 , ' Loss of Nuclear Envelope Integrity and Increased Oxidant Production Cause DNA Damage in Adult Hearts Deficient in PKP2 : A Molecular Substrate of ARVC ' , Circulation , vol. 146 , no. 11 , pp. 851-867 .
- Publication Year :
- 2022
-
Abstract
- Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by high propensity to life-threatening arrhythmias and progressive loss of heart muscle. More than 40% of reported genetic variants linked to ARVC reside in the PKP2 gene, which encodes the PKP2 protein (plakophilin-2). Methods: We describe a comprehensive characterization of the ARVC molecular landscape as determined by high-resolution mass spectrometry, RNA sequencing, and transmission electron microscopy of right ventricular biopsy samples obtained from patients with ARVC with PKP2 mutations and left ventricular ejection fraction >45%. Samples from healthy relatives served as controls. The observations led to experimental work using multiple imaging and biochemical techniques in mice with a cardiac-specific deletion of Pkp2 studied at a time of preserved left ventricular ejection fraction and in human induced pluripotent stem cell-derived PKP2-deficient myocytes. Results: Samples from patients with ARVC present a loss of nuclear envelope integrity, molecular signatures indicative of increased DNA damage, and a deficit in transcripts coding for proteins in the electron transport chain. Mice with a cardiac-specific deletion of Pkp2 also present a loss of nuclear envelope integrity, which leads to DNA damage and subsequent excess oxidant production (O-2(.-) and H2O2), the latter increased further under mechanical stress (isoproterenol or exercise). Increased oxidant production and DNA damage is recapitulated in human induced pluripotent stem cell-derived PKP2-deficient myocytes. Furthermore, PKP2-deficient cells release H2O2 into the extracellular environment, causing DNA damage and increased oxidant production in neighboring myocytes in a paracrine manner. Treatment with honokiol increases SIRT3 (mitochondrial nicotinamide adenine dinucleotide-dependent protein deacetylase sirtuin-3) activity, reduces oxidant levels and DNA damage in vitro and in vivo, reduces collagen abundan
Details
- Database :
- OAIster
- Journal :
- Perez-Hernandez , M , van Opbergen , C J M , Bagwan , N , Vissing , C R , Marron-Linares , G M , Zhang , M , Vega , E T , Sorrentino , A , Drici , L , Sulek , K , Zhai , R , Hansen , F B , Christensen , A H , Boesgaard , S , Gustafsson , F , Rossing , K , Small , E M , Davies , M J , Rothenberg , E , Sato , P Y , Cerrone , M , Jensen , T H L , Qvortrup , K , Bundgaard , H , Delmar , M & Lundby , A 2022 , ' Loss of Nuclear Envelope Integrity and Increased Oxidant Production Cause DNA Damage in Adult Hearts Deficient in PKP2 : A Molecular Substrate of ARVC ' , Circulation , vol. 146 , no. 11 , pp. 851-867 .
- Notes :
- application/pdf, English
- Publication Type :
- Electronic Resource
- Accession number :
- edsoai.on1349073169
- Document Type :
- Electronic Resource