The renin-angiotensin system mediates changes in vascular structure and function in hypertension andprobably other pathophysiological conditions. Angiotensin II (Ang II) is known to produce oxidative stress, butlittle is known about mechanisms that protect the vasculature from Ang II. The overall goal of this project is todefine molecular mechanisms that protect blood vessels from oxidative stress and endothelial dysfunctionproduced by Ang II.Components of the inflammatory response are activated within the vessel wall in many diseases includinghypertension. Ang II activates multiple inflammatory mechanisms within vascular cells. Although emergingevidence suggests a major protective role for the anti-inflammatory cytokine interleukin-10 (IL-10) in vascularbiology, nothing is known regarding a potential protective role for IL-10 in hypertension.
Our first Aim i s touse gene targeted mice to examine the role of IL-10 in oxidative stress and vascular dysfunction producedby Ang II.Although oxidative stress appears to play a key role in hypertension, very little is known about thefunctional importance of superoxide dismutase (SOD) isoforms in hypertension. The manganese isoform ofSOD (Mn-SOD) is expressed in relatively high levels in endothelium and is increased in hypertension andinflammation, but the functional importance of this expression is completely unknown.
Our second Aim i s touse Mn-SOD deficient and transgenic mice to examine the role of Mn-SOD in the vascular oxidative stressproduced by Ang II.Recent data suggest that iNOS may be an important mediator of vascular dysfunction. iNOS is expressedin vascular cells in response to inflammatory stimuli and Ang II. In our third Aim, we will use iNOS deficientmice to examine the hypothesis that expression of iNOS contributes to oxidative stress and endothelialdysfunction in response to Ang II.We have obtained preliminary data that support these hypotheses. Our focus on mechanisms of oxidativestress and endothelial dysfunction seems appropriate considering that endothelial dysfunction has a majorimpact on the vessel wall and has emerged as an independent predictor of clinical events. Studies in thisproject should provide new insight into mechanisms of vascular protection against Ang II includinginflammatory related mechanisms in hypertension. The studies fit well within several major themes of thisprogram - oxidative stress, inflammation, and vascular dysfunction.
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