It has become increasingly apparent that the capacitance function of larger vessels, and in particular the aorta, modulates hemodynamics by accommodating a portion of stroke volume during systole, reducing systolic pressure and maintaining systemic perfusion during diastole. Common clinical conditions, including aging, insulin resistance, diabetes and hypertension per se are associated with loss of this elastance function, predisposing to systolic hypertension. The mechanisms underlying these changes remain unknown;however clinical studies have suggested that inflammation and oxidative injury are associated with parameters of arterial stiffening. Biochemical and experimental studies have also implicated reactive oxygen species in modifications of elastin and collagen that would promote arterial stiffening. Prior work from our laboratory and others demonstrated that reactive oxygen species play a critical role in hypertension. More recently, we have shown that the adaptive immune system and the cytokine IL-17 are important in the genesis of hypertension. In the proposed studies, we will employ unique, genetically modified mice that permit us to increase or decrease vascular smooth muscle levels of reactive oxygen species to study how these contribute to arterial stiffening, vascular collagen and elastin content and biochemical modifications of these. We will accomplish this by using mice we have made that allow us to delete either the extracellular superoxide dismutase (SOD3) or the NADPH oxidase subunit p22phox. We hypothesize that increasing vascular oxidant injury by deleting SOD3 will enhance, while inhibiting oxidant stress by deleting p22phox will prevent arterial stiffening. In other studies, we will test the hypothesis that adaptive immunity and in particular T cells and the cytokine IL-17 contribute to arterial stiffening. We propose that RAG-1-/- and IL-17-/- mice will not develop arterial stiffening during angiotensin II infusion, but that adoptive transfer of T cells will promote arterial stiffening in these animals. Finally, we hypothesize that arterial stiffening, by transmitting increased pressure to target tissues, such as distal vessels and the kidney;will promote an inflammatory response and T cell activation, which further increases blood pressure. To test this hypothesis, we will cross mice heterozygotic for elastin deficiency (Eln mice) with RAG-1-/- mice. We postulate that these animals will have reduced blood pressure compared to Eln mice, and that adoptive transfer of T cells will restore blood pressure in these animals. These studies will provide new information regarding the etiology of arterial stiffening. Our combined expertise in the physiology of hypertension, connective tissue biochemistry and cardiovascular histomorphology place us in a unique position to pursue these directions of research.
Project Narrative: Arterial stiffening is an important mediator of systolic hypertension;however the mechanisms responsible for changes in large vessel compliance remain undefined. This project will test the hypothesis that oxidative injury and the adaptive immune system interact to increase arterial stiffness. These studies promise to provide new information regarding hypertension, vascular disease and how alterations in arterial compliance predispose to inflammation.
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|Titze, Jens; Dahlmann, Anke; Lerchl, Kathrin et al. (2014) Spooky sodium balance. Kidney Int 85:759-67|
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|Trott, Daniel W; Thabet, Salim R; Kirabo, Annet et al. (2014) Oligoclonal CD8+ T cells play a critical role in the development of hypertension. Hypertension 64:1108-15|
|Madhur, Meena S; Harrison, David G (2013) Senescent T cells and hypertension: new ideas about old cells. Hypertension 62:13-5|
|Harrison, David G (2013) The mosaic theory revisited: common molecular mechanisms coordinating diverse organ and cellular events in hypertension. J Am Soc Hypertens 7:68-74|
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|Pech, Vladimir; Thumova, Monika; Dikalov, Sergey I et al. (2013) Nitric oxide reduces Clýýý absorption in the mouse cortical collecting duct through an ENaC-dependent mechanism. Am J Physiol Renal Physiol 304:F1390-7|
|Wiig, Helge; Schroder, Agnes; Neuhofer, Wolfgang et al. (2013) Immune cells control skin lymphatic electrolyte homeostasis and blood pressure. J Clin Invest 123:2803-15|
|Itani, Hana A; Dikalov, Sergey; Harrison, David G (2013) Knock, knock: who's there?: Nox1. Circulation 127:1850-2|
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