Defective protein repair under methionine sulfoxide A deletion drives autophagy and ARE-dependent gene transcription

Abstract

ObjectiveReduction of oxidized methionines is emerging as a major protein repair pathway. The lack of methionine sulfoxide reductase A (MsrA) exacerbates cardiovascular disease phenotypes driven by increased oxidative stress. However, the role of MsrA on maintaining cellular homeostasis in the absence of excessive oxidative stress is less well understood.Methods and resultsConstitutive genetic deletion of MsrA increased formation of p62-containing protein aggregates, activated autophagy, and decreased a marker of apoptosis in vascular smooth muscle cells (VSMC). The association of Keap1 with p62 was augmented in MsrA-/- VSMC. Keap1 targets the transcription factor Nrf2, which regulates antioxidant genes, for proteasomal degradation. However, in MsrA-/- VSMC, the association of Nrf2 with Keap1 was diminished. Whereas Nrf2 mRNA levels were not decreased in MsrA-/- VSMC, we detected decreased ubiquitination of Nrf2 and a corresponding increase in total Nrf2 protein in the absence of biochemical markers of oxidative stress. Moreover, nuclear-localized Nrf2 was increased under MsrA deficiency, resulting in upregulation of Nrf2-dependent transcriptional activity. Consequently, transcription, protein levels and enzymatic activity of glutamate-cysteine ligase and glutathione reductase were greatly augmented in MsrA-/- VSMC.SummaryOur findings demonstrate that reversal of methionine oxidation is required for maintenance of cellular homeostasis in the absence of increased oxidative stress. These data provide the first link between autophagy and activation of Nrf2 in the setting of MsrA deletion.

Acacetin exerts antioxidant potential against atherosclerosis through Nrf2 pathway in apoE−/− Mice

“…Surprisingly, we found that both the Nrf2 and downstream HO‐1 expression levels were significantly decreased when MsrA was knocked down by msra siRNA (Figure 3I,L). These results differ from that of Pennington et al's findings, 39 which instead presented an increase in Nrf2, Keap1 and p62 expression in vascular smooth muscle cells from MsrA −/− mice, and in turn proposed that the abundant p62 competes with Nrf2 for binding to Keap1. However, we found an observable increase in Keap1 expression levels when MsrA was down‐regulated in EA.hy926 cells, suggesting that MsrA may be involved in the canonical step of Keap1‐mediated Nrf2 ubiquitination degradation.…”

Acacetin exert antioxidant potential against atherosclerosis through Nrf2 pathway in apoE-/- mice

“…3I and 3L). These results differ from that of Pennington et al's findings [40], which instead presented an increase in Nrf2, Keap1 and p62 expression in vascular smooth muscle cells from MsrA −/− mice, and in turn proposed that the abundant p62 competes with…”

The transcription factor Sox7 modulates endocardiac cushion formation contributed to atrioventricular septal defect through Wnt4/Bmp2 signaling

“…Wei-J et al reported that Ppp1r3b polymorphisms were associated with serum LDL-C levels, the risk of coronary artery disease and ischemic stroke in the Southern Chinese Han population 33 . The lack of Msra exacerbates cardiovascular disease phenotypes driven by increased oxidative stress 34 . Nevertheless, only Sox7 is related to cardiovascular development 12 , 16 , 17 .…”