Deletion of Methionine Sulfoxide Reductase A Does Not Affect Atherothrombosis but Promotes Neointimal Hyperplasia and Extracellular Signal-Regulated Kinase 1/2 Signaling

Abstract

Objective Emerging evidence suggests that methionine oxidation can directly affect protein function and may be linked to cardiovascular disease. The objective of this study was to define the role of the methionine sulfoxide reductase A (MsrA) in models of vascular disease and identify its signaling pathways. Approach and Results MsrA was readily identified in all layers of the vascular wall in human and murine arteries. Deletion of the MsrA gene did not affect atherosclerotic lesion area in apolipoprotein E-deficient mice, and had no significant effect on susceptibility to experimental thrombosis after photochemical injury. In contrast, the neointimal area after vascular injury due to complete ligation of the common carotid artery was significantly greater in MsrA-deficient compared to control mice. In aortic vascular smooth muscle cells (VSMC) lacking MsrA, cell proliferation was significantly increased due to accelerated G1/S transition. In parallel, cyclin D1 protein and cdk4/cyclin D1 complex formation and activity were increased in MsrA-deficient VSMC, leading to enhanced Rb phosphorylation and transcription of E2F. Finally, MsrA-deficient VSMC exhibited greater activation of ERK1/2 that was caused by increased activity of the Ras/Raf/MEK signaling pathway. Conclusion Our findings implicate MsrA as a negative regulator of VSMC proliferation and neointimal hyperplasia after vascular injury through control of the Ras/Raf/MEK/ERK1/2 signaling pathway.

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

“…However, progress towards dissecting Msr function has been hampered by the absence of straightforward systematic methods to identify Msr protein substrates [46] , [47] , [48] . Therefore, Msrs have been investigated in mammalian models of diseases that are driven by high oxidative stress, such as asthma, neurodegenerative diseases and various forms of cardiovascular disease [18] , [30] , [49] , [50] , [51] , [52] , [53] . Methionine oxidation also occurs with environmental stress, for example diesel exhaust particles.…”

“…Mouse aortic smooth muscle cells were isolated from 2 to 3 10–12-week old male and female mice per isolation by enzymatic dispersion as previously described [30] . Briefly, the adventitia was removed by incubating with elastase (0.74 U/ml) and collagenase (1 mg/ml) in HBSS (#14175–095, Gibco) and peeled away from the medial layers of the aorta.…”

“…These findings prompted us to hypothesize that MsrA deficiency may upregulate the accumulation of p62-containing protein aggregates, augment autophagy and Nrf2-dependent ARE gene transcription under baseline conditions when oxidative stress levels are not elevated. Our previous work focused on MsrA and its effect in the response to mechanical vascular injury, with a particular emphasis on smooth muscle cell proliferation and migration [30] . Here, we investigated whether MsrA deletion affects smooth muscle survival and repair processes at baseline.…”

Protein methionine oxidation augments reperfusion injury in acute ischemic stroke

“…Oxidation of protein methionine residues by ROS can alter the structure and function of key vascular proteins, potentially contributing to vascular disease. For example, recent studies have demonstrated that methionine sulfoxide reductase A (MsrA), an intracellular enzyme that reverses protein methionine oxidation, can protect from atherosclerosis and neointimal hyperplasia in mice (15–17). MsrA also protects from cardiac and renal ischemia/reperfusion injury in mouse models (18, 19).…”

Recent Advances in the Genetics of Atherothrombotic Disease and Its Determinants

“…90 Deletion of methionine sulfoxide reductase A on the ApoE-null background did not affect atherothrombosis, but did promote neointimal hyperplasia and extracellular signal-regulated kinase 1/2 signaling. 91 In ApoE-null mice fed a Western diet, the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine significantly attenuated atherosclerotic lesions, because of abnormal methylation status of specific target genes and effects on vascular smooth muscle cell dedifferentiation and remodeling. 92 Finally, hypertensive ApoE-null mice developed fibrotic aortic valve stenosis.…”