Increased superoxide production causes coronary endothelial dysfunction and depressed oxygen consumption in the failing heart

Abstract

This study examined whether increased superoxide (O2−·) production contributes to coronary endothelial dysfunction and decreased coronary blood flow (CBF) in congestive heart failure (CHF). To test this hypothesis, the effects of the low-molecular-weight SOD mimetic M40401 on CBF and myocardial oxygen consumption (MV̇o2) were examined in dogs during normal conditions and after CHF was produced by 4 wk of rapid ventricular pacing. The development of CHF was associated with decreases of left ventricular (LV) systolic pressure, maximum first derivative of LV pressure, MV̇o2, and CBF at rest and during treadmill exercise as well as endothelial dysfunction with impaired vasodilation in response to intracoronary acetylcholine. M40401 increased CBF (18 ± 5%, P < 0.01) and MV̇o2 (14 ± 6%, P < 0.01) in CHF dogs and almost totally reversed the impaired CBF response to acetylcholine. M40401 had no effect on acetylcholine-induced coronary vasodilation, CBF, or MV̇o2 in normal dogs. Western blot analysis demonstrated that extracellular SOD (EC-SOD) was significantly decreased in CHF hearts, whereas mitochondrial Mn-containing SOD was increased. Cytosolic Cu/Zn-containing SOD was unchanged. Both increased O2−· production and decreased vascular O2−· scavenging ability by EC-SOD could have contributed to endothelial dysfunction in the failing hearts.

Extracellular superoxide dismutase protects the heart against oxidative stress and hypertrophy after myocardial infarction

“…Thus, CHF is associated with decreased EC-SOD protein content or activity [9][10][11] and overexpression of EC-SOD has been reported to protect the heart against ischemia-reperfusion injury [25,26] (an effect not enhanced by administration of catalase, demonstrating that protection was dependent upon removal of superoxide but not hydrogen peroxide). In contrast to these previous reports in failing hearts, in the present study EC-SOD protein was significantly increased in the periinfarct region, and SOD1 protein was increased in both the peri-infarct and remote regions of the infarcted hearts.…”

“…Patients in whom EC-SOD binding to endothelial cells is decreased as the result of substitution of arginine-213 by glycine (R213G) have an increased incidence of hypertension [7] and increased risk of ischemic heart disease [7,8], implying that impaired EC-SOD binding or decreased myocardial EC-SOD content can increase the vulnerability to cardiovascular disease. Several recent studies have demonstrated that EC-SOD expression is decreased in the failing heart, and this was associated with evidence of increased myocardial oxidative stress and endothelial dysfunction [9][10][11]. However, whether EC-SOD can influence ventricular oxidative stress and remodeling after MI remains unknown.…”

Endothelial Mitochondria

“…129 Administration of a low-molecular-weight superoxide dismutase mimetic to dogs protects against pacing-induced heart failure and preserves coronary endothelial function. 130 Antioxidants (eg, vitamin C) seem to improve endothelial functionality and reduce the inflammatory response in patients with heart failure. 127 As mentioned, endogenous NO may regulate myocardial mitochondrial oxidative phosphorylation by directly competing with oxygen at complex IV (see above, under section Endothelial NO Production).…”

Role of inducible nitric oxide synthase in cardiac function and remodeling in mice with heart failure due to myocardial infarction

“…In vitro studies have shown that iNOS not only produces NO but is also capable of generating superoxide independently of NO (39). Moreover, not only is superoxide itself toxic to the heart, but it also leads to the formation of H 2 O 2 , which may also be toxic (5,16,24,29). Thus blockade or deletion of iNOS may decrease not only NO production but also formation of superoxide, in turn reducing generation of H 2 O 2 .…”