Involvement of Nox2 NADPH oxidase in adverse cardiac remodeling after myocardial infarction.
Oxidative stress plays an important role in the development of cardiac remodeling after myocardial infarction (MI), but the sources of oxidative stress remain unclear. We investigated the role of Nox2-containing reduced nicotinamide-adenine dinucleotide phosphate oxidase in the development of cardiac remodeling after MI. Adult Nox2(-/-) and matched wild-type (WT) mice were subjected to coronary artery ligation and studied 4 weeks later. Infarct size after MI was similar in Nox2(-/-) and WT mice. Nox2(-/-) mice exhibited significantly less left ventricular (LV) cavity dilatation and dysfunction after MI than WT mice (eg, echocardiographic LV end-diastolic volume: 75.7+/-5.8 versus 112.4+/-12.3 microL; ejection fraction: 41.6+/-3.7 versus 32.9+/-3.2%; both P<0.05). Similarly, in vivo LV systolic and diastolic functions were better preserved in Nox2(-/-) than WT mice (eg, LV dP/dt(max): 7969+/-385 versus 5746+/-234 mm Hg/s; LV end-diastolic pressure: 12.2+/-1.3 versus 18.0+/-1.8 mm Hg; both P<0.05). Nox2(-/-) mice exhibited less cardiomyocyte hypertrophy, apoptosis, and interstitial fibrosis; reduced increases in expression of connective tissue growth factor and procollagen 1 mRNA; and smaller increases in myocardial matrix metalloproteinase-2 activity than WT mice. These data suggest that the Nox2-containing reduced nicotinamide-adenine dinucleotide phosphate oxidase contributes significantly to the processes underlying adverse cardiac remodeling and contractile dysfunction post-MI.
Looi
Yee H
YH
Department of Cardiology, King's College London School of Medicine, James Black Centre, 125 Coldharbour Ln, London SE5 9NU, United Kingdom.
Grieve
David J
DJ
Siva
Anjana
A
Walker
Simon J
SJ
Anilkumar
Narayana
N
Cave
Alison C
AC
Marber
Michael
M
Monaghan
Mark J
MJ
Shah
Ajay M
AM
D000818:Animals; D017209:Apoptosis; D006328:Cardiac Catheterization; D006332:Cardiomegaly / Q000209:etiology / Q000378:metabolism; D004452:Echocardiography; D005355:Fibrosis; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000150:complications / Q000175:diagnosis / Q000473:pathology / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013194:Staining and Labeling; D016019:Survival Analysis; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D020257:Ventricular Remodeling
D008562:Membrane Glycoproteins; D012333:RNA, Messenger; C002744:3-nitrotyrosine; D014443:Tyrosine; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; D020778:Matrix Metalloproteinase 2