Submitted on January 25, 2008
Revised on August 5, 2008
Accepted on August 23, 2008
Role of Oxidative Stress in Multiparity-Induced Endothelial Dysfunction
Huda E Tawfik1, Johnathan Cena, Richard Schulz1, and Susan Kaufman1*
1 University of Alberta
* To whom correspondence should be addressed. E-mail: susan.jacobs{at}ualberta.ca.
Multiparity is associated with increased risk of cardiovascular disease. We tested whether multiparity induces oxidative stress in rat vascular tissue. Coronary arteries and thoracic aorta were isolated from multiparous and age-matched virgin rats. Relaxation to acetylcholine (ACh) and sodium nitroprusside (SNP) was measured by wire myography. We also tested the effect of the superoxide dismutase mimetic MnTE2PyP (30µM), the NADPH oxidase inhibitor apocynin (10µM), and the peroxynitrite scavenger FeTPPs (10µM) on ACh-mediated relaxation in coronary arteries. Vascular superoxide anion was measured using the luminol derivative L-012, and NO generation by the Griess reaction. Multiparity reduced maximal response and sensitivity to ACh in coronary arteries (Emax: multiparous 49%±3 vs. virgins 95%±3; EC50: multiparous 135±1nM vs. virgins 60±1nM), and in aortic rings (Emax: multiparous 38%±3 vs. virgins 79%±4; EC50: multiparous 160±2nM vs. virgins 90±3nM). Coronary arteries from the two groups relaxed similarly to SNP. Superoxide anion formation was significantly higher in both coronary arteries (2.8-fold increase) and aorta (4.1-fold increase) from multiparous rats compared with virgins. In multiparous rats, incubation with MnTE2PyP, apocynin, and FeTPPs improved maximal relaxation to ACh (MnTE2PyP: 74±5%; vehicle: 41±5%; Apocynin: 73±3% vs. vehicle: 41±3%; FeTPPs: 72±3% vs. vehicle: 46±3%) and increased sensitivity (EC50: MnTE2PyP: 61±0.5nM vs. vehicle: 91±1nM; Apocynin: 45±3nM vs. vehicle: 91±6nM; FeTPP: 131±2nM vs. vehicle: 185±1nM). Multiparity also reduced total nitrate/nitrite levels (multiparous: 2.5±2µmole/mg protein vs. virgins: 7±1µmole/mg protein), and eNOS protein levels (multiparous: 0.53±0.1protein/actin vs. virgins: 1.0±0.14protein/actin). These data suggest that multiparity induces endothelial dysfunction through decreased nitric oxide bioavailability and increased ROS formation.
