title: Proteasome inhibition attenuates heart failure during the late stages of pressure overload through alterations in collagen expression.
abstract: Although the role of the ubiquitin-proteasome system (UPS) in cardiac hypertrophy induced by pressure overload has been consistently studied, the fundamental importance of the UPS in cardiac fibrosis has received much less attention. Our previous study found that proteasome inhibitor (MG132) treatment attenuated cardiac fibrosis and heart failure during the early and middle stages of pressure overload. However, the effects of this inhibitor on late-stage pressure overload hearts remain unclear and controversial. The present study was designed to investigate the effects and possible mechanisms of MG132 on cardiac fibrosis and dysfunction during the late stages of pressure overload. Male Sprague Dawley rats with abdominal aortic constriction (AAC) or a sham operation received an intraperitoneal injection of MG132 (0.1 mg kg⁻¹ day⁻¹) or vehicle for 16 weeks. Left ventricular (LV) function, collagen deposition and Ang II levels were evaluated at study termination. Ang II-stimulated adult rat cardiac fibroblasts were utilized to examine the effects of MG132 on collagen synthesis and the relationship between the renin-angiotensin-aldosterone system (RAAS) and the UPS. MG132 treatment attenuated ventricular dysfunction by suppressing cardiac fibrosis rather than inhibiting cardiac hypertrophy during the late-stages of pressure overload. We also found that Ang II activates UPS in the heart and MG132 attenuates Ang II-induced collagen synthesis via suppression of the NF-κB/TGF-β/Smad2 signaling pathways. Proteasome inhibition therefore could provide a new promising therapeutic strategy to prevent cardiac fibrosis and progression of heart failure even during the late-stages of pressure overload.
authors.affiliation: Department of Cardiology, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China.
authors.forename: Yuedong
authors.initials: Y
authors.lastname: Ma
authors.forename: Yili
authors.initials: Y
authors.lastname: Chen
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Baolin
authors.initials: B
authors.lastname: Chen
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.forename: Zhaojun
authors.initials: Z
authors.lastname: Xiong
authors.forename: Chengxi
authors.initials: C
authors.lastname: Zhang
authors.forename: Yugang
authors.initials: Y
authors.lastname: Dong
mesh_terms: D000804:Angiotensin II / Q000097:blood / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects*; D005355:Fibrosis; D006333:Heart Failure / Q000209:etiology / Q000517:prevention & control*; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007976:Leupeptins / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D061988:Proteasome Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control
chemical_list: D007976:Leupeptins; D061988:Proteasome Inhibitors; D012333:RNA, Messenger; C508962:Tgfb1 protein, rat; D053773:Transforming Growth Factor beta1; D025801:Ubiquitin; D000804:Angiotensin II; D003094:Collagen; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde