Deubiquitinating enzyme CYLD mediates pressure overload-induced cardiac maladaptive remodeling and dysfunction via downregulating Nrf2.
Ubiquitin proteasome system (UPS) consists of ubiquitin, ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), ubiquitin ligases (E3s), proteasomes, and deubiquitinating enzymes (DUBs). Ubiquitin, E1s, several E2s, E3s, and proteasomes play an important role in the regulation of cardiac homeostasis and dysfunction; however, less is known about the role of DUBs in the heart. Here, we uncovered a crucial role of cyclindromatosis (CYLD), a DUB, in mediating cardiac maladaptive remodeling and dysfunction. CYLD expression was dramatically upregulated in the cardiomyocytes of hypertrophic and failing human and murine hearts. Knockout of CYLD improved survival rate and alleviated cardiac hypertrophy, fibrosis, apoptosis, oxidative stress, and dysfunction in mice that were subjected to sustained pressure overload induced by transverse aortic constriction. Deep sequencing and gene array analyses revealed that the most dramatically changed genes are those involving in the free radical scavenging pathway and cardiovascular disease, including fos, jun, myc, and nuclear factor erythroid-2 related factor 2 (Nrf2) in the heart. Moreover, knockdown of CYLD enhanced mitogen-activated protein kinase (MAPK) ERK- and p38-mediated expression of c-jun, c-fos, and c-myc, which govern Nrf2 expression in cardiomyocytes. The CYLD deficiency-induced suppression of reactive oxygen species (ROS) formation, death and hypertrophy in cardiomyocytes was blocked by additional knockdown of Nrf2. Taken together, our findings demonstrate for the first time that CYLD mediates cardiac maladaptive remodeling and dysfunction, most likely via enhancing myocardial oxidative stress in response to pressure overload. At the molecular level, CYLD interrupts the ERK- and p38-/AP-1 and c-Myc pathways to suppress Nrf2-operated antioxidative capacity, thereby enhancing oxidative stress in the heart.
Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China; Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, SC 29208, USA.
Hui
H
Wang
Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, SC 29208, USA.
Yimu
Y
Lai
Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, SC 29208, USA.
Bryan J
BJ
Mathis
Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China; Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, SC 29208, USA.
Wenjuan
W
Wang
Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China; Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, SC 29208, USA.
Siying
S
Li
Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China; Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, SC 29208, USA.
Chen
C
Qu
Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China; Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, SC 29208, USA.
Bin
B
Li
Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China; Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, SC 29208, USA.
Lei
L
Shao
Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China; Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, SC 29208, USA.
Haibo
H
Song
Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, SC 29208, USA.
Joseph S
JS
Janicki
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
Sao-Cong
SC
Sun
Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China.
Xing Li
XL
Wang
Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China. Electronic address: tangdq@sdu.edu.cn.
Dongqi
D
Tang
Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China; Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, SC 29208, USA. Electronic address: Taixing.Cui@uscmed.sc.edu.
Taixing
T
Cui
D000818:Animals; D006332:Cardiomegaly / Q000150:complications / Q000000981:diagnostic imaging / Q000201:enzymology / Q000503:physiopathology*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D000074749:Deubiquitinating Enzyme CYLD; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006333:Heart Failure / Q000150:complications / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D008297:Male; D018345:Mice, Knockout; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress; D011312:Pressure; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D016019:Survival Analysis; D018808:Transcription Factor AP-1 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000378:metabolism*; D014463:Ultrasonography; D015854:Up-Regulation; D020257:Ventricular Remodeling; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D051267:NF-E2-Related Factor 2; D016271:Proto-Oncogene Proteins c-myc; D018808:Transcription Factor AP-1; D025521:Tumor Suppressor Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C409984:CYLD protein, human; C511601:CYLD protein, mouse; C581019:CYLD protein, rat; D000074749:Deubiquitinating Enzyme CYLD; D043222:Ubiquitin Thiolesterase; D003546:Cysteine Endopeptidases
CYLD; Cardiomyopathy; Heart failure; Nrf2; Oxidative stress