During the past funding cycle, our research has emphasized the importance of the NAD(P)H oxidase as a source of reactive oxygen species and confirmed that it plays a crucial role in the hypertension caused by angiotensin II. In addition, we have shown that the extracellular superoxide dismutase (ecSOD) seems to play an important compensatory role in conditions associated with increased vascular oxidant stress, for example in angiotensin H-induced hypertension and in two transgenic mouse models tmice overexpressing either p22 phox or nox1). Very recently, we have found that mice lacking ecSOD, ecSOD mice, the hypertension caused by angiotensin II infusion is dramatically enhanced, again supporting a critical role of the ecSOD in modulating oxidant stress and hypertension. In the present studies, we plan to gain further insight into regulation of this enzyme and how it modulates blood pressure.
In aim 1, we will examine the hypothesis that H2O2 is responsible for the increase in ecSOD in response to angiotensin II. To accomplish this, we will treat vascular smooth muscle cells in culture with angiotensin II in the presence or absence of PEG-SOD or PEG-catalase. We will also study vascular smooth muscle cells that are deficient in p47 phox from p47 phox-/-mice and cells overexpressing catalase (Tg catvsmc mice). In vivo, we will examine the ability of angiotensin II to increase ecSOD expression in p47 phox-/- mice and Tg catvsmc mice. We anticipate that ecSOD expression will not be increased in p47 phox-/- mice or in Tg catvsmc mice.
In aims 2 and 3, we will examine mechanisms responsible for the augmented hypertension caused by angiotensin II in the ecSOD -/- mice.
In aim 2, we will examine the effect of angiotensin II on renal sodium excretion in wild-type and ecSOD / mice and examine the effect of a sodium free diet on blood pressure in these animals.
In aim 3, we will make use of a mouse that we have recently created that will allow vascular smooth muscle specific deletion of ecSOD and examine the effect of angiotensin II on blood pressure and renal sodium excretion in these mice. The effect of angiotensin II on vascular reactivity, superoxide production and nitric oxide bioavailability will be studied in these mice as well.
This aim will allow us to understand the relative importance of vascular vs. non-vascular sources of ecSOD in modulation of blood pressure and vascular tone. Finally, in aim 4, we will study the effect of deletion of ecSOD in mice overexpressing the NAD(P)H oxidase subunit p22 phox. These transgenic mice, which we created during the past funding period, have a modest increase in vascular free radical oxygen production and a 3-fold increase in ecSOD expression. We hypothesize that elimination of ecSOD in these mice will result in a hypertensive phenotype with a marked increase in vascular free radical oxygen production. Overall, these studies should further our knowledge of how vascular oxidant stress is modulated in vivo and in particular provide new information regarding the importance of the ecSOD in this process.
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