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En Face Detection of Nitric Oxide and Superoxide in Endothelial Layer of Intact Arteries
Published on: February 25, 2016
NADPH oxidase contributes to coronary endothelial dysfunction in the failing heart
Ping Zhang1, Mingxiao Hou, Yunfang Li
1Department of Medicine, University of Minnesota Health Sciences Center, Minneapolis, MN 55455, USA.
Abstract:
Increased reactive oxygen species (ROS) produced by the failing heart can react with nitric oxide (NO), thereby decreasing NO bioavailability. This study tested the hypothesis that increased ROS generation contributes to coronary endothelial dysfunction in the failing heart. Congestive heart failure (CHF) was produced in six dogs by ventricular pacing at 240 beats/min for 4 wk. Studies were performed at rest and during treadmill exercise under control conditions and after treatment with the NADPH oxidase inhibitor and antioxidant apocynin (4 mg/kg iv). Apocynin caused no significant changes in heart rate, aortic pressure, left ventricular (LV) systolic pressure, LV end-diastolic pressure, or maximum rate of LV pressure increase at rest or during exercise in normal or CHF dogs. Apocynin caused no change in coronary blood flow (CBF) in normal dogs but increased CBF at rest and during exercise in animals with CHF (P < 0.05). Intracoronary ACh caused dose-dependent increases of CBF that were blunted in CHF. Apocynin had no effect on the response to ACh in normal dogs but augmented the response to ACh in CHF dogs (P < 0.05). The oxidative stress markers nitrotyrosine and 4-hydroxy-2-nonenal were significantly greater in failing than in normal myocardium. Furthermore, coelenterazine chemiluminescence for O(2)(-) was more than twice normal in failing myocardium, and this difference was abolished by apocynin. Western blot analysis of myocardial lysates demonstrated that the p47(phox) and p22(phox) subunits of NADPH were significantly increased in the failing hearts, while real-time PCR demonstrated that Nox2 mRNA was significantly increased. The data indicate that increased ROS generation in the failing heart is associated with coronary endothelial dysfunction and suggest that NADPH oxidase may contribute to this abnormality.
Insights
Increased reactive oxygen species (ROS) in heart failure reduce nitric oxide (NO) availability. This study shows that the antioxidant apocynin improves coronary blood flow and endothelial function in failing hearts, suggesting NADPH oxidase is involved.
Area of Science:
- Cardiovascular Physiology
- Oxidative Stress Research
- Pharmacology
Background:
- Failing hearts produce increased reactive oxygen species (ROS), which can deplete nitric oxide (NO) and impair endothelial function.
- Coronary endothelial dysfunction is a hallmark of heart failure, impacting blood flow regulation.
- The role of specific ROS-generating enzymes, like NADPH oxidase, in this dysfunction requires further elucidation.
Purpose of the Study:
- To test the hypothesis that increased ROS generation contributes to coronary endothelial dysfunction in a canine model of congestive heart failure (CHF).
- To investigate the therapeutic potential of the NADPH oxidase inhibitor and antioxidant, apocynin, in improving endothelial function and coronary blood flow (CBF) in CHF.
Main Methods:
- Congestive heart failure (CHF) was induced in dogs via ventricular pacing.
- Coronary blood flow (CBF) responses to acetylcholine (ACh) were measured at rest and during exercise, before and after apocynin administration.
- Oxidative stress markers (nitrotyrosine, 4-hydroxy-2-nonenal) and ROS production (chemiluminescence) were assessed in myocardial tissue.
- Expression levels of NADPH oxidase subunits (p47phox, p22phox, Nox2) were analyzed using Western blot and real-time PCR.
Main Results:
- Apocynin treatment did not alter hemodynamics but significantly increased CBF at rest and during exercise in CHF dogs.
- Apocynin augmented the blunted CBF response to acetylcholine in CHF dogs, indicating improved endothelial function.
- Myocardial tissue from CHF dogs showed elevated oxidative stress markers and increased ROS production, which were reduced by apocynin.
- Increased expression of NADPH oxidase subunits (p47phox, p22phox) and Nox2 mRNA was observed in failing hearts.
Conclusions:
- Increased ROS generation, likely mediated by NADPH oxidase, is associated with coronary endothelial dysfunction in heart failure.
- Inhibition of NADPH oxidase with apocynin improves coronary blood flow and endothelial function in a failing heart model.
- Targeting ROS production via NADPH oxidase inhibition represents a potential therapeutic strategy for heart failure complications.
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