MG132, a proteasome inhibitor, attenuates pressure-overload-induced cardiac hypertrophy in rats by modulation of mitogen-activated protein kinase signals

Abstract

Proteasome inhibitors are involved in cell cycle control, growth and inflammatory signaling, and transcriptional regulation of mitotic cells. A recent study has suggested that specific proteasome inhibitor MG132 may suppress cardiomyocyte hypertrophy in vitro. However, the underlying molecular mechanisms are not clear. In this study, we investigated the effects of long-term MG132 treatment on cardiac hypertrophy and the related molecular mechanisms in vivo. MG132 (0.1 mg/kg/day) was intraperitoneally injected to rats with abdominal aortic banding (AAB) for 8 weeks. Results showed that treatment with MG132 significantly attenuated left ventricular (LV) myocyte area, LV weight/body weight, and lung weight/body weight ratios, decreased LV diastolic diameter and wall thickness, and increased fractional shortening in AAB rats. AAB induced the phosphorylation of ERK1/2, JNK1, and p38 in cardiac myocytes. The elevated phosphorylation levels of ERK1/2 and JNK1 in AAB rats were significantly reversed by MG132 treatment. In conclusion, our results suggested that long-term treatment with MG132 attenuates pressureoverload-induced cardiac hypertrophy and improves cardiac function in AAB rats through regulation of ERK1/2 and JNK1 signaling pathways.

Altered ubiquitin-proteasome signaling in right ventricular hypertrophy and failure

“…The results are in concordance with a number of studies on LVH remodeling in both mice and humans (33,49,63), in aging hearts (8), and ischemia-reperfusion injury (21,60) but is in discordance with other studies (5,12,20,32,45,46). The explanations for the varying responses in the LV have been debated (31,43) and may be related to differences in the animal models or in techniques used in assessing proteasome activity.…”

“…However, studies have been contradictory, showing either increased or decreased proteasomal enzyme activity in the afterload stressed LV (31, 43). Other models have demonstrated both cardioprotective (9, 21, 25, 59) and cardiotoxic (12,20,27,32,45,46) roles of the UPS via regulation of apoptosis, NF-B signaling, and oxidative stress.Although much is known about the molecular mechanisms of LVH and LV failure (LVF), the mechanisms underlying right ventricular (RV) hypertrophy (RVH) and RV failure (RVF) are less understood. RVH and RVF are a major cause of morbidity and mortality in patients with pulmonary hypertension and represent long-term risks for patients with surgically corrected congenital heart diseases such as tetralogy of Fallot, L-transposition of the great arteries, and hypoplastic left heart (4, 34).…”

“…However, studies have been contradictory, showing either increased or decreased proteasomal enzyme activity in the afterload stressed LV (31, 43). Other models have demonstrated both cardioprotective (9, 21, 25, 59) and cardiotoxic (12,20,27,32,45,46) roles of the UPS via regulation of apoptosis, NF-B signaling, and oxidative stress.…”

Original article Nigrostriatal pathway degeneration in rats after intraperitoneal administration of proteasome inhibitor MG-132

“…It has been reported that [19] in experimental inflammatory bo wel disease MG-132 in vivo reduced T cell-mediated intestinal inflammation but significantly suppressed cell migration and epithelial cell proliferation. MG-132 also has an influence on the cardiovascular system [8,29,34]. In a low dose (0.1 mg/kg) MG-132 administered intraperitoneally once per day even for 2 or 8 weeks may effectively prevent cardiac remodelling and dysfunction in pressure-overloaded hearts without marked drug toxicity [29].…”

Changes in cardiac structure and function in rats immunized by angiotensin type 1 receptor peptides

“…The heart tissue was cut into 5 mm sections, and stained with hematoxylin and eosin (HE). Cardiomyocytes cross-sectional area was determined using the method described by Chen et al [16]. Cardiomyocytes size from each group was evaluated by measuring the cross-sectional area of cells using the image analysis system (CIAS-1000, China Daheng Group, Inc., Beijing, China).…”