Foxp3 Tregs are recruited to the retina to repair pathological angiogenesis.

Neovascular retinopathies are major causes of vision loss; yet treatments to prevent the condition are inadequate. The role of regulatory T cells in neovascular retinopathy is unknown. Here we show that in retinopathy regulatory T cells are transiently increased in lymphoid organs and the retina, but decline when neovascularization is established.

Inhibition of the Nuclear Receptor RORγ and Interleukin-17A Suppresses Neovascular Retinopathy: Involvement of Immunocompetent Microglia.

Objective: Although inhibitors of vascular endothelial growth factor (VEGF) provide benefit for the management of neovascular retinopathies, their use is limited to end-stage disease and some eyes are resistant. We hypothesized that retinoic acid-related orphan nuclear receptor γ (RORγ) and its downstream effector, interleukin (IL)-17A, upregulate VEGF and hence are important treatment targets for neovascular retinopathies.

Approach And Results: Utilizing a model of oxygen-induced retinopathy, confocal microscopy and flow cytometry, we identified that retinal immunocompetent cells, microglia, express IL-17A.

HMGB1 binds to activated platelets via the receptor for advanced glycation end products and is present in platelet rich human coronary artery thrombi.

High mobility group box 1 (HMGB1) acts as both a nuclear protein that regulates gene expression, as well as a pro-inflammatory alarmin that is released from necrotic or activated cells. Recently, HMGB1-expression in human atherosclerotic plaques was identified. Therapeutic blockade of HMGB1 reduced the development of diet-induced atherosclerosis in ApoE knockout mice.

Prorenin stimulates a pro-angiogenic and pro-inflammatory response in retinal endothelial cells and an M1 phenotype in retinal microglia.

Angiogenesis and inflammation are causative factors in the development of neovascular retinopathies. These processes involve the retinal endothelium and the retinal immune cells, microglia. The renin-angiotensin system contributes to retinal injury via the actions of the type 1 angiotensin receptor (AT1R).

Retinal vasculopathy is reduced by dietary salt restriction: involvement of Glia, ENaCα, and the renin-angiotensin-aldosterone system.

Objective: Neovascularization and vaso-obliteration are vision-threatening events that develop by interactions between retinal vascular and glial cells. A high-salt diet is causal in cardiovascular and renal disease, which is linked to modulation of the renin-angiotensin-aldosterone system. However, it is not known whether dietary salt influences retinal vasculopathy and if the renin-angiotensin-aldosterone system is involved.

Protective role for Toll-like receptor-9 in the development of atherosclerosis in apolipoprotein E-deficient mice.

Objective: Atherosclerosis is driven by inflammatory reactions that are shared with the innate immune system. Toll-like receptor-9 (TLR9) is an intracellular pattern recognition receptor of the innate immune system that is currently under clinical investigation as a therapeutic target in inflammatory diseases. Here, we investigated whether TLR9 has a role in the development of atherosclerosis in apolipoprotein E-deficient (ApoE(-/-)) mice.

NADPH oxidase, NOX1, mediates vascular injury in ischemic retinopathy.

Aims: Ischemic retinal diseases such as retinopathy of prematurity are major causes of blindness due to damage to the retinal microvasculature. Despite this clinical situation, retinopathy of prematurity is mechanistically poorly understood. Therefore, effective preventative therapies are not available.

A novel mouse model of atherosclerotic plaque instability for drug testing and mechanistic/therapeutic discoveries using gene and microRNA expression profiling.

Rationale: The high morbidity/mortality of atherosclerosis is typically precipitated by plaque rupture and consequent thrombosis. However, research on underlying mechanisms and therapeutic approaches is limited by the lack of animal models that reproduce plaque instability observed in humans.

Objective: Development and use of a mouse model of plaque rupture that reflects the end stage of human atherosclerosis.

Reactive oxygen species, Nox and angiotensin II in angiogenesis: implications for retinopathy.

Pathological angiogenesis is a key feature of many diseases including retinopathies such as ROP (retinopathy of prematurity) and DR (diabetic retinopathy). There is considerable evidence that increased production of ROS (reactive oxygen species) in the retina participates in retinal angiogenesis, although the mechanisms by which this occurs are not fully understood. ROS is produced by a number of pathways, including the mitochondrial electron transport chain, cytochrome P450, xanthine oxidase and uncoupled nitric oxide synthase.

Cytokine therapy with interleukin-2/anti-interleukin-2 monoclonal antibody complexes expands CD4+CD25+Foxp3+ regulatory T cells and attenuates development and progression of atherosclerosis.

Background: CD4+CD25+Foxp3+ regulatory T cells (Tregs) attenuate atherosclerosis, but their therapeutic application by adoptive transfer is limited by the need for their expansion in vitro and limited purity. Recently, an interleukin (IL)-2/anti-IL-2 neutralizing monoclonal antibody (IL-2/anti-IL-2 mAb) complex has been shown to expand these Tregs. We examined the capacity of a modified IL-2/anti-IL-2 mAb treatment to expand Tregs and inhibit both the progression and development of developed atherosclerosis.

Epigenetic modification of the norepinephrine transporter gene in postural tachycardia syndrome.

Objective: The postural tachycardia syndrome (POTS) has multiple symptoms, chief among which are tachycardia, weakness, and recurrent blackouts while standing. Previous research has implicated dysfunction of the norepinephrine transporter. A coding mutation in the norepinephrine transporter gene (SLC6A2) sequence has been reported in 1 family kindred only.

The retinal renin-angiotensin system: roles of angiotensin II and aldosterone.

In the present review we examine the experimental and clinical evidence for the presence of a local renin-angiotensin system within the retina. Interest in a pathogenic role for the renin-angiotensin system in retinal disease originally stemmed from observations that components of the pathway were elevated in retina during the development of certain retinal pathologies. Since then, our knowledge about the contribution of the RAS to retinal disease has greatly expanded.

B1a B lymphocytes are atheroprotective by secreting natural IgM that increases IgM deposits and reduces necrotic cores in atherosclerotic lesions.

Rationale: Aggravated atherosclerosis in B lymphocyte-deficient chimeric mice and reduced atherosclerosis after transfer of unfractionated spleen B lymphocytes into splenectomized mice have led to the widely held notion that B lymphocytes are atheroprotective. However, B lymphocytes can be pathogenic, because their depletion by anti-CD20 antibody ameliorated atherosclerosis, and transfer of B2 lymphocytes aggravated atherosclerosis. These observations raise the question of the identity of the atheroprotective B-lymphocyte population.

CD4⁺CD25⁺Foxp3⁺ regulatory T cells suppress cardiac fibrosis in the hypertensive heart.

Background: CD4⁺CD25⁺Foxp3⁺ regulatory T cells (Tregs) are potent inhibitors of inflammation and autoimmune diseases. Because inflammation has been associated with development of cardiac fibrosis in experimental hypertension, here we investigated whether adoptively transferred Tregs would inhibit development of cardiac fibrosis initiated by elevating blood pressure.

Methods: Cardiac fibrosis was induced in mice by constricting the aorta between the two carotid arteries.

High-mobility group box protein 1 neutralization reduces development of diet-induced atherosclerosis in apolipoprotein e-deficient mice.

Objective: High-mobility group box protein 1 (HMGB1) is a DNA-binding protein and cytokine highly expressed in atherosclerotic lesions, but its pathophysiological role in atherosclerosis is unknown. We investigated its role in the development of atherosclerosis in ApoE-/- mice.

Methods And Results: Apolipoprotein E-deficient (ApoE-/-) mice fed a high-fat diet were administered a monoclonal anti-HMGB1 neutralizing antibody, and the effects on lesion size, immune cell accumulation, and proinflammatory mediators were assessed using Oil Red O, immunohistochemistry, and real-time polymerase chain reaction.

Conventional B2 B cell depletion ameliorates whereas its adoptive transfer aggravates atherosclerosis.

Atherosclerosis is a chronic inflammatory arterial disease characterized by focal accumulation of lipid and inflammatory cells. It is the number one cause of deaths in the Western world because of its complications of heart attacks and strokes. Statins are effective in only approximately one third of patients, underscoring the urgent need for additional therapies.

Darbepoetin-mediated cardioprotection after myocardial infarction involves multiple mechanisms independent of erythropoietin receptor-common beta-chain heteroreceptor.

Background And Purpose: Darbepoetin, a long-acting erythropoietin derivative, attenuates cardiomyocyte apoptosis and improves short-term (3 days) cardiac function, but the mechanisms responsible are unknown. We investigated potential mechanisms by which darbepoetin exerts cardioprotection following myocardial infarction in mice and the significance of the erythropoietin receptor (EPOR)-common beta-chain (c-beta-chain) heteroreceptor.

Experimental Approach: Mice underwent 60 min coronary occlusion followed by treatment with vehicle or a single dose of darbepoetin.

NKT cell subsets mediate differential proatherogenic effects in ApoE-/- mice.

Objective: NKT cells promote atherogenesis, but the subtypes responsible have not been identified. We investigated 2 major NKT cell subtypes (CD4+ and DN NKT) in ApoE-/- mice rendered NKT cell-deficient by day-3 neonatal thymectomy (3dTx).

Methods And Results: Atherosclerosis development was studied in thymectomized ApoE-/- mice fed a high-fat diet with/without adoptively transferred NKT cells.

A novel antioxidant 3,7-dihydroxy-isoflav-3-ene (DHIF) inhibits neointimal hyperplasia after vessel injury attenuating reactive oxygen species and nuclear factor-kappaB signaling.

Reactive oxygen species (ROS) contribute to neointimal smooth muscle proliferation by yet to be defined mechanisms. We examined the effects of a novel isoflavone 3,7-dihydroxy-isoflav-3-ene (DHIF) on development of neointimal lesions in relation to ROS elevations and cell signaling in injured arteries. Carotid arteries of rabbits treated with vehicle or DHIF were injured with a balloon catheter and effects on proliferation, apoptosis, vessel structure, ROS, NF-kappaB activation, cyclooxygenase and gene expression examined.

Altered sympathetic nervous reactivity and norepinephrine transporter expression in patients with postural tachycardia syndrome.

Background: Clinical observations in patients with postural tachycardia syndrome (POTS) suggest abnormal sympathetic nervous system activity and a dysfunction of the norepinephrine (NE) transporter (NET).

Methods And Results: We examined sympathetic nervous system responses to head-up tilt by combining NE plasma kinetics measurements and muscle sympathetic nerve activity recordings and by quantifying NET protein content in peripheral sympathetic nerves in patients with POTS compared with that in controls. POTS patients had an elevated heart rate during supine rest (81+/-2 bpm versus 66+/-2 bpm in healthy subjects [HS], P<0.

Understanding the role of transforming growth factor-beta1 in intimal thickening after vascular injury.

Intimal thickening is the most important cause of in-stent restenosis. The pathology of intimal thickening is attributable to a local inflammatory response after vascular injury which results in the production of cytokines. Transforming growth factor-beta1 (TGF-beta1) is a profibrotic cytokine that is involved in the induction of intimal thickening.

The genetic basis for altered blood vessel function in disease: large artery stiffening.

The progressive stiffening of the large arteries in humans that occurs during aging constitutes a potential risk factor for increased cardiovascular morbidity and mortality, and is accompanied by an elevation in systolic blood pressure and pulse pressure. While the underlying basis for these changes remains to be fully elucidated, factors that are able to influence the structure and composition of the extracellular matrix and the way it interacts with arterial smooth muscle cells could profoundly affect the properties of the large arteries. Thus, while age and sex represent important factors contributing to large artery stiffening, the variation in growth-stimulating factors and those that modulate extracellular production and homeostasis are also being increasingly recognized to play a key role in the process.

Inhibition of fibroblast growth factor receptor signaling attenuates atherosclerosis in apolipoprotein E-deficient mice.

Objective: To determine the significance of fibroblast growth factor receptor (FGFR) expression for the development of atherosclerotic lesions in apoE-deficient (apoE-/-) mice.

Methods And Results: ApoE-/- mice fed a high-fat diet were administered the FGFR tyrosine kinase inhibitor SU5402 (25 mg/kg/d sc), which inhibited neointima growth by 85%. We measured its effects on lesion size at the aortic sinus, macrophage and smooth muscle cell (SMC) accumulation, the expression of monocyte chemotactic and retention factors, as well as its effects on FGFR expression/phosphorylation.