LETTER TO THE EDITOR: REPLY
NADPH oxidose in the failing human heart: Reply
Ajay M. Shah, MD, FRCP, FAHA* and
Christophe Heymes, PhD*
* Department of Cardiology, GKT School of Medicine, Bessemer Road, London SE5 9PJ, United Kingdom
ajay.shah{at}kcl.ac.uk
We thank Dr. Krijnen and colleagues for their interest in our report (1). The data, presented at the American Heart Association scientific sessions in 2002 (2), build upon prior experimental studies from our group and others (see Ref. 1). Although Krijnen et al. (3) discuss some parallels between our study and their recent interesting publication, several important differences should be emphasized.
The NAD(P)H oxidase is a multisubunit complex that requires not only a core catalytic Nox subunit but also several other components (p22phox, p47phox, p40phox, rac) for its function (4). Clear evidence of NAD(P)H oxidase expression and activity requires both the demonstration of multiple subunits and evidence of biochemical activity, as provided in our report (1). In addition, analysis of expression based solely on immunoblotting or immunohistochemistry is complicated by the fact that several Nox isoforms have recently been reported (4). Ideally, antibody-based methods should be complemented by RNA-based analyses (1). The best approach in experimental studies may be to employ gene-modified models (5).
With respect to NAD(P)H oxidase activation, this is recognized to occur through posttranslational modifications of one or more subunits (e.g., phosphorylation of p47phox) and/or altered expression levels (4). In our opinion, comments on mechanisms of activation of this complex enzyme based solely on qualitative analyses of Nox2 by immunohistochemistry are probably unwarranted. Our study found no change in overall tissue expression level of the four main oxidase subunits in end-stage chronic heart failure, whereas immunofluorescence studies indicated a translocation of p47phox to the cardiomyocyte sarcolemma where gp91phox was also present (1). Nevertheless, activation mechanisms of the oxidase remain speculative.
Finally, the condition we studied (chronic nonischemic congestive heart failure) (1) is quite distinct from the focus of Krijnen's report (acute myocardial infarction) (3). The NADPH oxidase subunit expression, cellular localization, stimuli for activation, and activation mechanisms could well be significantly different among these conditions.
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References
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1. Heymes C, Bendall JK, Ratajczak P, et al. Increased myocardial NADPH oxidase activity in human heart failure. J Am Coll Cardiol. 2003;41:2164–2171[Abstract/Free Full Text]
2. Heymes C, Bendall JK, Ratajczak P, et al. Increased NADPH oxidase-mediated superoxide production in human heart failure: potential role in left ventricular dysfunction. (abstr)Circulation. 2002;106:II202
3. Krijnen PAJ, Meischl C, Hack CE, et al. Increased Nox2 expression in human cardiomyocytes after acute myocardial infarction. J Clin Pathol. 2003;56:194–199[Abstract/Free Full Text]
4. Griendling KK, Sorescu D, Ushio-Fukai M. NAD(P)H oxidase. Role in cardiovascular biology and disease. Circ Res. 2000;86:494–501[Abstract/Free Full Text]
5. Bendall JK, Cave AC, Heymes C, Gall N, Shah AM. Pivotal role of gp91phox-containing NADPH oxidase in angiotensin II induced cardiac hypertrophy. Circulation. 2002;105:293–296[Abstract/Free Full Text]
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