Research focus: To discover immune and inflammatory mechanisms responsible for hypertension.
Hypertension affects one third of the Western population and another third has pre-hypertension. This condition is also a major cause of morbidity and mortality, leading to stroke, myocardial infarction, renal failure and heart failure. This end organ damage is largely due to inflammation, characterized by infiltration of T cells and macrophages in the kidney and vasculature. Surprisingly, T cells are essential for full development of hypertension, and T cell derived cytokines including IFN-g, IL-17 and IFN-g contribute to both renal and vascular dysfunction. We have discovered novel mechanisms responsible for T cell activation in hypertension and are developing therapeutic approaches to treat this disease. Some of the projects in the laboratory include:
Examining the roles of isoketals as neoantigens in hypertension: Isoketals, or gamma ketoaldehydes are oxidation products of arachidonic acid. These rapidly adduct to lysines and modify self-proteins such that they become antigenic. We find that isoketals accumulate in dendritic cells and are presented in the context of MHCI by these cells. The accumulation of isoketals is associated with a striking increase in cytokine production by DCs and an increase in co-stimulatory molecules. These DCs also drive T cell activation, and ultimately hypertension.
Understanding the role of the Dendritic Cell NADPH oxidase in hypertension: We have produced mice with LoxP sites flanking exon 5 of the NADPH oxidase subunit p22phox. By crossing these mice with CD11c Cre, we have produce mice with a dysfunctional NADPH oxidase in the DC. We hypothesize that the absence of the NADPH oxidase in DCs will prevent the accumulation of isoketals, reduce DC activation and ultimately reduce hypertension.
Understanding the role of vascular NADPH oxidase in hypertension: By crossing our p22phoxloxp/loxpmice with endothelial or vascular smooth muscle specific Cre recombinase, we are able to prevent ROS formation in key cells of the vessel wall. We have also overexpressed p22phox in vascular smooth muscle, and these mice develop T cell activation as they age and a consequent T-cell dependent form of hypertension. We hypothesize that isoketal-adducted proteins are shed by vascular cells and are cross-presented by DCs.
Understanding the role of CD8+ T cells and CD8+ T cell memory in response to repeated hypertensive stimuli. Repeated exposures to hypertensive stimuli is common, and we have found that these lead to striking elevations of blood pressure and T cells activation. We are studying the role of CD70, which interacts with CD27 on CD8+ T cells and leads to formation of memory cells. We have also produced mice in which we can repeatedly activate angiotensin II production via an inducible transgene to facilitate these studies.
Understanding mechanisms of aortic stiffening: A key cause of hypertension is stiffening of the aorta, which leads to loss of its Windkessel function. We have found that T cells and their production of IL-17 mediate this, leading to a striking deposition of collagen in the vascular adventitia. Our recent studies show that Sca-1 cells in the adventitia, some of which arise from the bone marrow, produce collagen in response to chronic angiotensin II infusion.
Understanding the role of central signaling in the genesis of inflammation in hypertension: In prior studies, we have obtained strong evidence that the central nervous system plays a critical role in activating T cells in hypertension. We produced AV3V lesions in the brain, which block sympathetic outflow from the brain, and these prevent T cells activation in response to angiotensin II. We have also deleted p22phox from the subfornical organ of the brain, also preventing hypertension. We are studying how sympathetic nerves activate DCs and formation of tissue isoketals. These studies involve intra-cerebral injections of adenoviruses encoding Cre recombinase in our p22phoxloxp/loxpmice and other mice we have made with loxP sites flanking the extracellular SOD to either block or increase sympathetic outflow in hypertension. Our readouts in these studies include both evidence of T cell and DC activation.
The Harrison and Madhur laboratories closely collaborate. Please see Dr. Meena Madhur’s laboratory description for additional information.