Abstract 730: Targeted Disruption of SOD1 Significantly Promotes Vascular Remodeling Induced by Periadventitial Injury: Phenotypes of SOD1 Deficient Mice and eNOS Deficient Mice
Background: Oxidative stress mediated by oxidants has been implicated in the pathogenesis of cardiovascular disease. Copper/zinc SOD (SOD1) is believed to play a major role in antioxidant defense; therefore, we examined the physiological and pathological cardiovascular phenotypes of SOD1-deficient mice (SOD−/−), and compared them with phenotypes of wild type mice (WT) and eNOS deficient mice (eNOS−/−) to clarify the role of SOD1 in the cardiovascular system.
Methods and Results:
SOD−/− had lower heart weights than WT and eNOS−/−(SOD−/−: 2.82±0.07; WT: 3.13±0.05; eNOS−/−: 3.19±0.14 mg/g, respectively). SOD−/− had lower blood pressure (BP) than WT, while eNOS−/− had higher BP (SOD−/−: 100.7±1.0; WT: 111.1±0.9; eNOS−/−: 141.6±1.1 mmHg, respectively). Relaxation of carotid arteries with acetylcholine was mildly impaired in SOD−/− when compared with WT, while it was completely ablated in eNOS−/−. Collectively, these data indicate that SOD1 plays a minor role in blood pressure regulation and vascular endothelial function compared with eNOS.
Next, we examined vascular remodeling induced by periadventitial cuff-injury. In comparison with WT, there were more CD45 positive cells and TUNEL positive cells in the arteries of SOD−/− on Day 10. Four weeks after cuff replacement, 3-nitrotyrosine levels, a marker of peroxynitrite production, in injured arteries were significantly higher in SOD−/− than WT. The number of PCNA positive cells were increased, and neointimal formation was dramatically enhanced in SOD−/−; moreover, intimal/medial area ratio was markedly increased in SOD−/− when compared with WT or with eNOS−/− (SOD−/−: 2.23±0.07; WT:0.44±0.05; eNOS−/−: 0.52±0.07, respectively). These data indicate that SOD1 plays a more important role than eNOS in vascular remodeling.
In our in vitro study utilizing primary cultures of vascular smooth muscle cells (VSMCs), the rate of apoptotic cells was increased in VSMCs of SOD−/− compared to VSMCs of WT. This higher susceptibility to apoptosis in VSMCs may contribute to the higher degree of vascular remodeling in SOD−/−.
Conclusion: SOD1 plays a more important role in vascular remodeling than eNOS, while SOD1 plays a minor role in hypertension and vascular endothelial dysfunction.