So far, cardiovascular and renal diseases have brought us not only huge economic burden but also serious society problems. Since effective therapeutic strategies are still limited, to find new methods for the prevention or therapy of these diseases is important. Oxidative stress has been found to play a critical role in the initiation and progression of cardiovascular and renal diseases. In addition, activation of nuclear-factor-E2-related-factor-2- (Nrf2-) antioxidant-responsive element (ARE) signaling pathway protects cells and tissues from oxidative damage. As a proteasomal inhibitor, MG132 was reported to activate Nrf2 expression and function, which was accompanied with significant preventive and/or therapeutic effect on cardiovascular and renal diseases under most conditions; therefore, MG132 seems to be a potentially effective drug to be used in the prevention of oxidative damage. In this paper, we will summarize the information available regarding the effect of MG132 on oxidative stress-induced cardiovascular and renal damage, especially through Nrf2-ARE signaling pathway.
The World Health Organization reports that chronic diseases as the leading cause of mortality in the world cause approximately 17 million people to die prematurely each year and keep steadily growing [
Epidemiological studies have shown several risk factors for patients with CVD and CKD, such as heredity [
There are highly regulated cellular defense systems, including the redox-sensitive nuclear-factor-E2-related-factor-2- (Nrf2-) antioxidant-responsive element (ARE) pathway. Nrf2 is a transcription factor to regulate the expression of a battery of antioxidant genes and other cytoprotective phase II detoxifying enzymes through binding ARE [
ROS, a necessary evil of aerobic life, are routinely produced as a byproduct of aerobic metabolism, oxidative phosphorylation, environmental stressors, disease, or even natural aging process [
There is an upsurge of interest in Nrf2-ARE system because it plays a key role in the cell’s response to oxidative stress [
(a) Nrf2/Keap1-ARE signaling pathway under physical condition and (b) oxidative stress condition. ARE: antioxidant-responsive element; Cys: cysteine; Keap1: Kelch-like ECH-associated protein 1; Nrf2: E2-related factor 2; Ub: ubiquitin.
When exposed to various stimuli such as oxidative stress, certain antioxidants, and chemopreventive agents, the Nrf2/Keap1 complex will be disrupted by modifying two (Cys273 and Cys288) of the 25 cysteine residues of Keap1 [
Modification of the Nrf2/Keap1 complex and Nrf2 nuclear translocation is important to Nrf2-ARE-pathway-dependent gene expression, and several signaling pathways are associated with these processes. For example, one component of these pathways is MAPKs. Both extracellular signal-regulated kinase (ERK) and p38MAPK have been found to induce Nrf2 translocation and HO-1 expression through diallyl sulfide in HepG2 cells [
Proteins in eukaryotic cells are continually being synthesized and degraded. Two proteolytic systems, the lysosomal systems and UPS, are mainly responsible for this homeostasis. The lysosomal system is the principal mechanism for degrading proteins with long half-life and is the only system in cells for degrading organelles and large protein aggregates or inclusions [
The UPS consists of three parts: the 76-amino acid protein ubiquitin, the multisubunit complex 26S proteasome, and three enzymes, including ubiquitin-activating (E1), ubiquitin-conjugating (E2), and ubiquitin-ligase (E3) which are involved in a 3-step enzymatic cascade process [
The process of target protein degeneration by UPS in eukaryotic cells (a) and mechanism of MG132 activate Nrf2/Keap1-ARE signaling pathway (b). Abbreviations: ARE: antioxidant-responsive element; Cys: cysteine; E1: ubiquitin-activating; E2: ubiquitin-conjugating; E3: ubiquitin-ligase; Keap1: Kelch-like ECH-associated protein 1; Nrf2: E2-related factor 2; Ub: ubiquitin.
MG132 (Z-Leu-Leu-Leu-CHO), a peptide aldehyde proteasome inhibitor, was constructed by Roca et al. in 1994 and has been widely used in proteasome biology, allowing for the identification of new therapeutic targets and the development of novel therapeutic strategies. MG132 is a substrate analogue and potent transition-state inhibitor and mainly exhibits the chymotrypsin-like activity of the proteasome [
The stabilization of Nrf2 by proteasome inhibition and subsequent transcriptional activation of its downstream genes have been shown in different cell types in earlier studies [
Despite that MG132 inhibition of proteasome results in an elevation of Nrf2 expression, the compensative induction of proteasome activity was also noticed. For instance, elevated proteasome subunit synthesis upon proteasome inhibition by MG132 is well conserved in human squamous cells [
With regard to CVD, many of the pathogenic components of the disease are associated with oxidative stress, such as inflammation, LDL oxidation, and endothelial dysfunction. Overproduction and accumulation of ROS severely damage DNA, proteins, and lipids, resulting in further tissue damage and organ dysfunction. Compelling evidence supports the idea that supraphysiological levels of ROS (or called oxidative stress) play an important role in the pathophysiology of various CVDs, including endothelial dysfunction [
Our previous study indicated that high glucose could lead to ROS generation in both primary neonatal and adult cardiomyocytes from wild-type mouse heart. Whereas, in Nrf2 knockout cells from Nrf2 knockout mice, ROS were significantly higher under basal conditions and high glucose markedly further increased ROS production in concentration- and time-dependent manners [
In a similar study, we treated STZ-induced diabetic mice with sulforaphane at 0.5 mg/kg daily in five days of each week for 3 months. Sulforaphane treatment completely prevented diabetes-induced aortic pathogenic changes by attenuating oxidative stress, inflammation, and fibrosis in the aorta [
Similar to CVD, oxidative stress is also the major player in the process of many kidney diseases, including acute kidney injury (AKI) [
Previous work has indicated that impaired renal function in hypercholesterolemic pigs is improved by chronic proteasome inhibition with MLN-273 [
Antifibrotic effect of MG132 at low doses has been observed in rat renal fibroblasts and mesangial cells [
A recent study from our group suggested that therapeutic effect of MG132 on diabetic cardiomyopathy is associated with its suppression of proteasomal activities [
The therapeutic effect of MG132 on diabetic nephropathy was also reported by our group [
It should be mentioned that whether cells have beneficial response to MG132 also depend on several factors, including the type of cells, the dose of MG132, and the exposure time. Contrast to the studies discussed above, several studies in cardiac myocytes showed an opposite conclusion. Exposure of myocytes to high doses of MG132 (10
Although MG132 protects cardiovascular and renal damage from oxidative stress predominantly via Nrf2-ARE signaling pathway, other possible mechanisms should not be ignored. Among these mechanisms, the relatively well-studied one is I
Accumulating observation has illustrated that a great range of cardiovascular and renal diseases have been associated with oxidative stress. Given that Nrf2-ARE signaling pathway plays critical roles in preventing oxidative stress-associated injury, Nrf2 activators are supposed to be used clinically as a new strategy. In a phase 2, double-blind, randomized, placebo-controlled clinic trial, Dinkova-Kostova et al. used bardoxolone methyl, which has the ability to activate Nrf2 [
The cited works from the laboratories of the authors were supported in part by the Basic Research Award from American Diabetes Association (1-11-BA-17 to L. Cai) and the National Natural Science Foundation of China (81200525 to W. Cui). No potential conflict of interests relevant to this paper was reported.