title: Activation of the cardiac proteasome promotes angiotension II-induced hypertrophy by down-regulation of ATRAP.
abstract: Proteasomal degradation is critical to maintaining cardiac function and is altered in various diseases. Angiotensin II (Ang II) acts as a growth factor to induce cardiac growth. Here we aimed to test whether proteasome is involved in the development of Ang II-induced cardiac hypertrophy and dissect its molecular mechanisms. Cardiac hypertrophy was induced by Ang II infusion (1000 ng/kg/min) using mini-osmotic pumps. Starting 1 day before implantation, the mice were injected with the proteasome inhibitor bortezomib (BTZ, 50 μg/kg, 3 times per week) or with vehicle. After 14 days, the pool of ubiquitinated proteins was reduced but the protein expression of proteasome subunits (including β1i, β2i and β5/β5i) was markedly up-regulated in left ventricular hypertrophy versus control, which was accompanied by a significant increase in proteasome activities. Furthermore, Ang II-treated mice showed a significant increase in blood pressure but decrease in cardiac contractile function, and significant left ventricular hypertrophy, fibrosis and inflammation, which were all attenuated in BTZ-treated mice. Mechanistically, these beneficial effects were associated with the inhibition of degradation of angiotensin II type 1 receptor-associated protein (ATRAP) and inactivation of AT1R-mediated p38 MAPK and STAT3 signaling pathways. In conclusion, our data indicate that the activation of proteasome is required for the Ang II-induced cardiac hypertrophy, and suggest that the inhibition of proteasome activity by BTZ could be a potential therapeutic strategy for the treatment of cardiac hypertrophy and other heart diseases.
authors.affiliation: Department of Physiology and Pathophysiology, AnZhen Hospital, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, School of Basic Medical Sciences, China; Department of Cardiology, Chaoyang Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Physiology and Pathophysiology, AnZhen Hospital, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, School of Basic Medical Sciences, China; Department of Cardiology, Chaoyang Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, China.
authors.forename: Hong-Xia
authors.initials: HX
authors.lastname: Wang
authors.affiliation: Department of Physiology and Pathophysiology, AnZhen Hospital, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, School of Basic Medical Sciences, China; Department of Cardiology, Chaoyang Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, China.
authors.forename: Qiu-Yue
authors.initials: QY
authors.lastname: Han
authors.affiliation: Department of Physiology and Pathophysiology, AnZhen Hospital, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, School of Basic Medical Sciences, China; Department of Cardiology, Chaoyang Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, China.
authors.forename: Wen-Jun
authors.initials: WJ
authors.lastname: Li
authors.affiliation: Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, China.
authors.forename: Yun-Long
authors.initials: YL
authors.lastname: Zhang
authors.affiliation: Department of Physiology and Pathophysiology, AnZhen Hospital, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, School of Basic Medical Sciences, China; Department of Cardiology, Chaoyang Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Du
authors.affiliation: Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, China. Electronic address: yunlong_xia@126.com.
authors.forename: Yun-Long
authors.initials: YL
authors.lastname: Xia
authors.affiliation: Department of Physiology and Pathophysiology, AnZhen Hospital, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, School of Basic Medical Sciences, China; Department of Cardiology, Chaoyang Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, China. Electronic address: hhli1995@yahoo.com.
authors.forename: Hui-Hua
authors.initials: HH
authors.lastname: Li
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000804:Angiotensin II; D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology* / Q000473:pathology*; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation; D005355:Fibrosis; D007249:Inflammation / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology*; D025821:Polyubiquitin / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology; D021122:Protein Subunits / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D057149:Ubiquitinated Proteins / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C119712:Agtrap protein, mouse; D061988:Proteasome Inhibitors; D021122:Protein Subunits; D044140:Receptor, Angiotensin, Type 1; D050796:STAT3 Transcription Factor; D057149:Ubiquitinated Proteins; D000804:Angiotensin II; D025821:Polyubiquitin; D048051:p38 Mitogen-Activated Protein Kinases; D046988:Proteasome Endopeptidase Complex
keywords: Angiotensin II; Angiotensin II type 1 receptor-associated protein; Bortezomib; Cardiac hypertrophy; Ubiquitin–proteasome system