Therapeutic effect of MG-132 on diabetic cardiomyopathy is associated with its suppression of proteasomal activities: roles of Nrf2 and NF-κB.

Abstract

MG-132, a proteasome inhibitor, can upregulate nuclear factor (NF) erythroid 2-related factor 2 (Nrf2)-mediated antioxidative function and downregulate NF-κB-mediated inflammation. The present study investigated whether through the above two mechanisms MG-132 could provide a therapeutic effect on diabetic cardiomyopathy in the OVE26 type 1 diabetic mouse model. OVE26 mice develop hyperglycemia at 2-3 wk after birth and exhibit albuminuria and cardiac dysfunction at 3 mo of age. Therefore, 3-mo-old OVE26 diabetic and age-matched control mice were intraperitoneally treated with MG-132 at 10 μg/kg daily for 3 mo. Before and after MG-132 treatment, cardiac function was measured by echocardiography, and cardiac tissues were then subjected to pathological and biochemical examination. Diabetic mice showed significant cardiac dysfunction, including increased left ventricular systolic diameter and wall thickness and decreased left ventricular ejection fraction with an increase of the heart weight-to-tibia length ratio. Diabetic hearts exhibited structural derangement and remodeling (fibrosis and hypertrophy). In diabetic mice, there was also increased systemic and cardiac oxidative damage and inflammation. All of these pathogenic changes were reversed by MG-132 treatment. MG-132 treatment significantly increased the cardiac expression of Nrf2 and its downstream antioxidant genes with a significant increase of total antioxidant capacity and also significantly decreased the expression of IκB and the nuclear accumulation and DNA-binding activity of NF-κB in the heart. These results suggest that MG-132 has a therapeutic effect on diabetic cardiomyopathy in OVE26 diabetic mice, possibly through the upregulation of Nrf2-dependent antioxidative function and downregulation of NF-κB-mediated inflammation.

• Authors: Yuehui Wang, Weixia Sun, Bing Du, Xiao Miao, Yang Bai, Ying Xin, Yi Tan, Wenpeng Cui, Bin Liu, Taixing Cui, Paul N Epstein, Yaowen Fu, Lu Cai
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 304 Issue 4 Pg. H567-78 (Feb 15 2013) ISSN: 1522-1539 [Electronic] United States
• PMID: 23220333 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• Cysteine Proteinase Inhibitors
• Leupeptins
• NF-E2-Related Factor 2
• NF-kappa B
• Nfe2l2 protein, mouse
• Proteasome Inhibitors
• benzyloxycarbonylleucyl-leucyl-leucine aldehyde

Topics

• Animals
• Antioxidants (metabolism)
• Cysteine Proteinase Inhibitors (therapeutic use)
• Diabetes Mellitus, Experimental (complications, pathology)
• Diabetes Mellitus, Type 1 (complications, pathology)
• Diabetic Cardiomyopathies (diagnostic imaging, drug therapy, physiopathology)
• Disease Models, Animal
• Female
• Gene Expression Regulation (drug effects, physiology)
• Hypertrophy, Left Ventricular (drug therapy, etiology, physiopathology)
• Leupeptins (therapeutic use)
• Mice
• Mice, Transgenic
• Myocarditis (drug therapy, physiopathology)
• NF-E2-Related Factor 2 (physiology)
• NF-kappa B (physiology)
• Oxidative Stress (drug effects, physiology)
• Proteasome Inhibitors (therapeutic use)
• Ultrasonography