Deficiency of methionine sulfoxide reductase A causes cellular dysfunction and mitochondrial damage in cardiac myocytes under physical and oxidative stresses.
Methionine sulfoxide reductase A (MsrA) is an enzyme that reverses oxidation of methionine in proteins. Using a MsrA gene knockout (MsrA(-/-)) mouse model, we have investigated the role of MsrA in the heart. Our data indicate that cellular contractility and cardiac function are not significantly changed in MsrA(-/-) mice if the hearts are not stressed. However, the cellular contractility, when stressed using a higher stimulation frequency (2Hz), is significantly reduced in MsrA(-/-) cardiac myocytes. MsrA(-/-) cardiac myocytes also show a significant decrease in contractility after oxidative stress using H(2)O(2). Corresponding changes in Ca(2+) transients are observed in MsrA(-/-) cardiomyocytes treated with 2Hz stimulation or with H(2)O(2). Electron microscope analyses reveal a dramatic morphological change of mitochondria in MsrA(-/-) mouse hearts. Further biochemical measurements indicate that protein oxidation levels in MsrA(-/-) mouse hearts are significantly higher than those in wild type controls. Our study demonstrates that the lack of MsrA in cardiac myocytes reduces myocardial cell's capability against stress stimulations resulting in a cellular dysfunction in the heart.
College of Medicine, Florida Atlantic University, Boca Raton, FL 33431, USA.
Changlong
C
Nan
Yuejin
Y
Li
Pierre-Yves
PY
Jean-Charles
Guozhen
G
Chen
Alexander
A
Kreymerman
Howard
H
Prentice
Herbert
H
Weissbach
Xupei
X
Huang
D000818:Animals; D002118:Calcium / Q000378:metabolism; D051150:Methionine Sulfoxide Reductases / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000201:enzymology / Q000502:physiology* / Q000648:ultrastructure; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000502:physiology* / Q000648:ultrastructure; D018384:Oxidative Stress; D013314:Stress, Mechanical
D051150:Methionine Sulfoxide Reductases; D002118:Calcium