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. 2009 May-Jun;18(3):156-66.
doi: 10.1016/j.carpath.2007.12.013. Epub 2008 Mar 4.

Cardiac oxidative stress and remodeling following infarction: role of NADPH oxidase

Wenyuan Zhao  1 , Dawn Zhao, Ran Yan, Yao Sun
Affiliations

Cardiac oxidative stress and remodeling following infarction: role of NADPH oxidase

Wenyuan Zhao et al. Cardiovasc Pathol. 2009 May-Jun.

Abstract

Background: There is growing recognition that oxidative stress plays a role in the pathogeneses of myocardial repair/remodeling following myocardial infarction (MI). Nicotinamide adenine denucleotide phosphate (NADPH) oxidase is a major source for cardiac reactive oxygen species production. Herein, we studied the importance of NADPH oxidase in development of cardiac oxidative stress and its induced molecular and cellular changes related to myocardial repair/remodeling.

Methods: MI was created by coronary artery ligation in C57/BL (wild type) and NADPH oxidase (gp91(phox)) knockout mice. Cardiac oxidative stress, inflammatory/fibrogenic responses, apoptosis, and hypertrophy were detected by in situ hybridization, immunohistochemistry, terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL), picrosirius red staining, and image analysis, respectively, at different stages post MI.

Results: In wild-type mice with MI, and compared to sham-operated animals, we observed significantly increased gp91(phox) and 3-nitrotyrosine, a marker of oxidative stress, in the infarcted myocardium; accumulated macrophages and myofibroblasts at the infarct site; abundant apoptotic myocytes primarily at border zones on Day 3; and numerous apoptotic inflammatory/myofibroblasts in the later stages. In addition, we detected significantly increased transforming growth factor beta1, tissue inhibitor of metalloprotease 2, and type 1 collagen gene expression; continuously increasing collagen volume in the infarcted myocardium; and hypertrophy in noninfarcted myocardium. Compared to wild-type mice with MI, we did not observe significant difference in infarct size/thickness, cardiac hypertrophy, myocyte apoptosis, inflammatory/fibrogenic responses, as well as cardiac oxidative stress in gp91(phox) knockout mice.

Conclusion: Our findings indicate that during NADPH oxidase deficiency, superoxide production can be compensated by other sources, which leads to cardiac oxidative stress and its related molecular/cellular events in the infarcted heart.

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Figures

Figure 1
Figure 1
Cardiac gp91phox gene expression in wild type mice. In sham-operated heart, low levels of gp91phox mRNA were present in both left and right ventricles (LV, RV) (panel A). On day 7 postMI, gp91phox mRNA levels were largely increased at the site of MI, but not in septum (S) and right ventricle (panel B). Cardiac gp91phox mRNA was not detectable in gp91phox knockout mice (panel C). Panel D shows temporal response of gp91phox mRNA in the infarcted myocardium. * p<0.05 vs controls (CTL).
Figure 2
Figure 2
Heart weight, infarct size and infarct thickness in wild type and gp91phox knockout (gp91phox-/-) mice.
Figure 3
Figure 3
Cells involved in cardiac repair following MI in wild type mice. ED-1+ macrophages, CD3+ lymphocytes and Ki67+ proliferating cells were rarely seen in the normal heart (panels A, C, and E, respectively). On day 7 postMI, macrophages were accumulated at the site of MI (panel B, brown), while only a few lymphocytes were seen in the same site (panel D, arrows). Abundant proliferating cells (brown) including fibroblast-like cells (arrows), vascular endothelial and smooth muscle cells (V), were present in the infarcted myocardium (panel F). α-SMA+ myofibroblasts were not present in the normal heart (panel G, arrows: α-SMA+ vascular smooth muscle cells). On day 7 postMI, myofibroblasts appeared and accumulated in the infarcted myocardium (panel H, brown).
Figure 4
Figure 4
Apoptosis in the infarcted mouse heart. Apoptotic cells were not observed in the normal mouse heart (panel A). Following MI, numerous apoptotic myocytes (bright spots) were seen in the infarcted myocardium on day 3 (panel B). Apoptotic inflammatory cells (panel C) and myofibroblasts (panel D) became evident in the infarcted myocardium of wild type mice on day 7 and 28, respectively. Temporal cardiac apoptosis data in both wild type and gp91phox knockout mice are shown in panel E.
Figure 5
Figure 5
Gene expression of profibrogenic mediators in the infarcted wild type mouse heart. Detected by in situ hybridization, low levels of TGF-β1 (panel A), TIMP-2 (panel C), and type I collagen (panel E) mRNAs are located in both left and right ventricles (LV, RV). On day 7 postMI, TGF-β1 (panel B), TIMP-2 (panel D), and type I collagen (panel F) mRNAs were largely increased in the infarcted myocardium.
Figure 6
Figure 6
Temporal response of cardiac TGF-β1, TIMP-2 and type I collagen gene expression in the infarcted heart of wild type and gp91phox knockout mice.
Figure 7
Figure 7
Cardiac collagen volume and 3-nitrotyrosine expression. A small amount of collagen (red) is present in the interstitial space (pane A, arrows). Following MI, collagen volume is largely increased at the site of MI on day 28 (pane B). Temporal response of collagen volume fraction at the site of MI in both wild type and gp91phox knockout mice is shown in panel C. On day 7 postMI, 3-nitrotyrosine is similarly expressed in the inflammatory cells at the site of MI in wild type and gp91phox knockout mice (panels D and E, respectively).
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