title: MG132 treatment attenuates cardiac remodeling and dysfunction following aortic banding in rats via the NF-κB/TGFβ1 pathway.
abstract: Although MG132, a proteasome inhibitor, is suggested to impede secondary cardiac remodeling after hypertension, the mechanism and optimal duration of treatment remain unknown. This study was designed to investigate the effects and possible mechanism of MG132 on hypertension-induced cardiac remodeling. Male Sprague-Dawley rats subjected to abdominal aortic constriction (AAC) or sham operation received an intraperitoneal injection of MG132 (0.1mgkg(-1)day(-1)) or vehicle over a 2- or 8-week period. In the end, left ventricular (LV) function was evaluated with echocardiography and pressure tracing. Collagen deposition within the LV myocardium was assessed with Masson's trichrome staining. Ubiquitin-proteasome system (UPS), NF-κB, I-κB, TGFβ1 and Smad2 within the LV tissue were evaluated. In addition, angiotensin II within both plasma and LV tissue was also examined. Compared with the sham groups, the vehicle-treated AAC group exhibited a higher angiotensin II level, LV/body weight ratio, septal and posterior wall thicknesses, and a markedly reduced cardiac function (P<0.05). Treatment with MG132 for 8 weeks attenuated these cardiac remodeling parameters and improved cardiac function (P<0.01). 2- and 8-week hypertension led to activation of UPS, which was followed by activation of NF-κB and increased expression of TGFβ1 and Smad2 (P<0.01). MG132 significantly inhibited NF-κB activity and down-regulate the levels of TGFβ1 and Smad2 expression by 2 and still at 8 weeks (P<0.01). Short- and long-term treatment with MG132 significantly attenuated hypertension-induced cardiac remodeling and dysfunction, which may be mediated by the NF-κB/TGFβ1 signaling pathway.
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, PR China. doctormayuedong@yahoo.com.cn
authors.forename: Yuedong
authors.initials: Y
authors.lastname: Ma
authors.forename: Baolin
authors.initials: B
authors.lastname: Chen
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Zhaojun
authors.initials: Z
authors.lastname: Xiong
authors.forename: Junyi
authors.initials: J
authors.lastname: Zeng
authors.forename: Yugang
authors.initials: Y
authors.lastname: Dong
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001012:Aorta, Abdominal / Q000473:pathology; D003094:Collagen / Q000378:metabolism; D003250:Constriction; D005355:Fibrosis; D006439:Hemodynamics / Q000187:drug effects; D006973:Hypertension / Q000000981:diagnostic imaging / Q000473:pathology* / Q000503:physiopathology*; D007976:Leupeptins / Q000494:pharmacology*; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis / Q000502:physiology*; D025801:Ubiquitin / Q000096:biosynthesis; D014463:Ultrasonography; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D007976:Leupeptins; D016328:NF-kappa B; D061988:Proteasome Inhibitors; D053773:Transforming Growth Factor beta1; D025801:Ubiquitin; D000804:Angiotensin II; D003094:Collagen; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde