Genetically Reduced Antioxidative Protection and Increased Ischemic Heart Disease Risk

Abstract

Background-Extracellular superoxide dismutase (EC-SOD) is an antioxidative enzyme found in high concentrations in the arterial wall. Two to three percent of all people in Denmark carry an R213G substitution, which increases plasma concentration 10-fold. This may reduce arterial wall EC-SOD concentrations, increase intimal LDL oxidation, and therefore may accelerate atherogenesis. Our primary hypothesis was that EC-SOD-R213G predisposes to ischemic heart disease (IHD). The secondary hypothesis was that EC-SOD-R213G offers predictive ability with respect to IHD beyond that offered by measurements of plasma EC-SOD and autoantibodies against oxidized LDL (oxLDL). Methods and Results-The primary hypothesis was tested in a prospective, population-based study of 9188 participants from The Copenhagen City Heart Study with 956 incident IHD events during 23 years of follow-up and retested cross-sectionally with independent case populations of patients with IHD (nϭ943) or ischemic cerebrovascular disease (ICVD) (nϭ617). Case populations were compared with unmatched IHD/ICVD-free control subjects from The Copenhagen City Heart Study (nϭ7992). The secondary hypothesis was tested by using a nested case-control study comparing patients with IHD (nϭ956) with age-and gender-matched control subjects (nϭ956). Age-and genderadjusted relative risk for IHD in heterozygotes (nϭ221, 2.4%) versus noncarriers (nϭ8965, 97.6%) was 1.5 (95% CI, 1.1 to 2.1). Retesting confirmed this: Age-and gender-adjusted odds ratios for IHD was 1.4 (1.0 to 2.0) and for ICVD 1.7 (1.1 to 2.7). Additional adjustment for plasma EC-SOD produced an odds ratio for IHD in heterozygotes versus noncarriers of 9.2 (1.2 to 72), whereas adjustment for autoantibodies against oxLDL produced an odds ratio of 2.5 (1.2 to 5.3). Conclusions-Heterozygosity for EC-SOD-R213G is associated with increased IHD risk. Genotyping offers predictive ability with respect to IHD beyond that offered by plasma EC-SOD and autoantibodies against oxLDL.

Extracellular superoxide dismutase (ecSOD) in vascular biology: an update on exogenous gene transfer and endogenous regulators of ecSOD

“…120 Also, the R213G gene variant was suggested to accelerate the progression of renal failure and atherosclerosis in uremic patients. 121 Finally, a study in Denmark detected a 2.3-fold increase in risk of ischemic heart disease in heterozygotes carrying ecSOD(R213G), with a 9-fold increase for plasma levels of ecSOD, 122 presumably because of increased in the vasculature of ecSOD(R213G) carriers.…”

Inactivation of Extracellular Superoxide Dismutase Contributes to the Development of High-Volume Hypertension

“…3 Consequently, a role of endogenous ecSOD for controlling NO bioavailability has been demonstrated in animal experiments 4 and a mutation of ecSOD which attenuates binding of the enzyme to matrix, is associated with an increased risk of cardiovascular fatalities. 5 It is unclear whether pharmacological application of human ecSOD confers protection against oxidative stress in the vasculature. Most studies reporting a beneficial effect were performed in rats.…”

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

“…As a result, EC-SOD binds to the surface of endothelial cells and the extracellular matrix which has a high abundance of heparan sulfate [6]. 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].…”