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.
Copyright © 2011 Elsevier Inc. All rights reserved.