Deubiquitinating enzyme CYLD mediates pressure overload-induced cardiac maladaptive remodeling and dysfunction via downregulating Nrf2

Autor: Dongqi Tang, Yimu Lai, Joseph S. Janicki, Xing Li Wang, Sao Cong Sun, Bin Li, Siying Li, Haibo Song, Wenjuan Wang, Taixing Cui, Hui Wang, Chen Qu, Bryan J. Mathis, Lei Shao
Rok vydání: 2015
Předmět:
Male
MAPK/ERK pathway
medicine.medical_specialty
NF-E2-Related Factor 2
Down-Regulation
Cardiomegaly
Biology
medicine.disease_cause
Models
Biological
p38 Mitogen-Activated Protein Kinases
Deubiquitinating enzyme
Deubiquitinating Enzyme CYLD
Proto-Oncogene Proteins c-myc
Downregulation and upregulation
Ubiquitin
Internal medicine
Pressure
medicine
Animals
Humans
Myocytes
Cardiac
Gene Silencing
Extracellular Signal-Regulated MAP Kinases
Molecular Biology
Ultrasonography
Heart Failure
Mice
Knockout
Pressure overload
Ventricular Remodeling
Myocardium
Tumor Suppressor Proteins
Survival Analysis
Rats
Up-Regulation
Cell biology
Transcription Factor AP-1
Cysteine Endopeptidases
Oxidative Stress
Endocrinology
Proteasome
Gene Knockdown Techniques
biology.protein
Cardiology and Cardiovascular Medicine
Ubiquitin Thiolesterase
Oxidative stress
Signal Transduction
Zdroj: Journal of Molecular and Cellular Cardiology. 84:143-153
ISSN: 0022-2828
DOI: 10.1016/j.yjmcc.2015.04.012
Popis: 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.
Databáze: OpenAIRE
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