In vivo proximity proteomics uncovers palmdelphin(PALMD)as a Z-disc-associated mitigator of isoproterenol-induced cardiac injury  

作　　者：Cong-ting Guo Blake DJardin Jun-sen Lin Rachelle LAmbroise Ze Wang Lu-zi Yang Neil Mazumdar Fu-jian Lu Qing Ma Yang-po Cao Can-zhao Liu Kai-long Li Xu-jie Liu Feng Lan Ming-ming Zhao Han Xiao Er-dan Dong William T.Pu Yu-xuan Guo 

机构地区：[1]School of Basic Medical Sciences,Institute of Cardiovascular Sciences,Peking University Health Science Center,Beijing 100191,China [2]Department of Cardiology,Boston Children’s Hospital,Boston,MA,USA [3]Harvard College,Harvard University,Cambridge,MA,USA [4]Institutes of Biomedical Sciences,Fudan University,Shanghai 200032,China [5]Department of Pharmacology,Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases,School of Medicine,Southern University of Science and Technology,Shenzhen 518055,China [6]Department of Cardiology,Translational Medicine Research Center,Zhujiang Hospital,Southern Medical University,Guangzhou 510280,China [7]Department of Biochemistry and Molecular Biology,Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function,School of Basic Medical Sciences,Peking University Health Science Center,Beijing 100191,China [8]Shenzhen Key Laboratory of Cardiovascular Disease,Fuwai Hospital Chinese Academy of Medical Sciences,Shenzhen 518057,China [9]Department of Cardiology and Institute of Vascular Medicine,Peking University Third Hospital,Beijing 100191,China [10]State Key Laboratory of Vascular Homeostasis and Remodeling,Peking University,Beijing 100191,China [11]Beijing Key Laboratory of Cardiovascular Receptors Research,NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides,Beijing 100191,China [12]Research Center for Cardiopulmonary Rehabilitation,University of Health and Rehabilitation Sciences Qingdao Hospital(Qingdao Municipal Hospital),School of Health and Life Sciences,University of Health and Rehabilitation Sciences,Qingdao 266071,China

出　　处：《Acta Pharmacologica Sinica》2024年第12期2540-2552,共13页中国药理学报（英文版）

基　　金：funded by the National Key R&D Program of China(2022YFA1104800);the National Natural Science Foundation of China(82222006);the Beijing Nova Program(20220484205)and Beijing Natural Science Foundation(7232094);supported by National Institute of Health(R01HL146634 and R01HL163937);supported by the Natural Science Foundation of China(82070235 and 92168113);the CAMs Innovation Fund for Medical Sciences(2021-12M-5-003);Haihe Laboratory of Cell Ecosystem Innovation Fund(HH22KYZX0047);supported by the National Natural Science Foundation of China(82170231);Guangdong Basic and Applied Basic Research Foundation(2023B1515020103).

摘　　要：Z-discs are core ultrastructural organizers of cardiomyocytes that modulate many facets of cardiac pathogenesis.Yet a comprehensive proteomic atlas of Z-disc-associated components remain incomplete.Here,we established an adeno-associated virus(AAV)-delivered,cardiomyocyte-specific,proximity-labeling approach to characterize the Z-disc proteome in vivo.We found palmdelphin(PALMD)as a novel Z-disc-associated protein in both adult murine cardiomyocytes and human pluripotent stem cell-derived cardiomyocytes.Germline and cardiomyocyte-specific Palmd knockout mice were grossly normal at baseline but exhibited compromised cardiac hypertrophy and aggravated cardiac injury upon long-term isoproterenol treatment.By contrast,cardiomyocyte-specific PALMD overexpression was sufficient to mitigate isoproterenol-induced cardiac injury.PALMD ablation perturbed the transverse tubule(T-tubule)-sarcoplasmic reticulum(SR)ultrastructures,which formed the Z-disc-associated junctional membrane complex(JMC)essential for calcium handling and cardiac function.These phenotypes were associated with the reduction of nexilin(NEXN),a crucial Z-disc-associated protein that is essential for both Z-disc and JMC structures and functions.PALMD interacted with NEXN and enhanced its protein stability while the Nexn mRNA level was not affected.AAV-based NEXN addback rescued the exacerbated cardiac injury in isoproterenol-treated PALMD-depleted mice.Together,this study discovered PALMD as a potential target for myocardial protection and highlighted in vivo proximity proteomics as a powerful approach to nominate novel players regulating cardiac pathogenesis.

关 键 词：proximity proteomics sarcomere Z-disc isoproterenol induced cardiac injury palmdelphin 

分 类 号：R541[医药卫生—心血管疾病]