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Jain D.,Heinrich Heine University Dusseldorf | Jain R.,Heinrich Heine University Dusseldorf | Eberhard D.,Heinrich Heine University Dusseldorf | Eglinger J.,Heinrich Heine University Dusseldorf | And 6 more authors.
Journal of Molecular Cell Biology | Year: 2012

Elderly patients often suffer from multiple age-related diseases. Here we show that the expression of DJ-1, an antioxidant protein with reduced expression in the central nervous system of patients with Parkinson's disease, is reduced in pancreatic islets of patients with type 2 diabetes mellitus (T2DM). In contrast, under non-diabetic conditions, DJ-1 expression increases in mouse and human islets during aging. In mouse islets, we show that DJ-1 prevents an increase in reactive oxygen species levels as the mice age. This antioxidant function preserves mitochondrial integrity and physiology, prerequisites for glucose-stimulated insulin secretion. Accordingly, DJ-1-deficient mice develop glucose intolerance and reduced β cell area as they age or gain weight. Our data suggest that DJ-1 is more generally involved in age-and lifestyle-related human diseases and show for the first time that DJ-1 plays a key role in glucose homeostasis and might serve as a novel drug target for T2DM. © 2012 The Author.

Planas-Paz L.,Heinrich Heine University Dusseldorf | Lammert E.,Heinrich Heine University Dusseldorf | Lammert E.,Paul Langerhans Group for Beta Cell Biology
Cellular and Molecular Life Sciences | Year: 2013

The lymphatic vasculature is essential for fluid homeostasis and transport of immune cells, inflammatory molecules, and dietary lipids. It is composed of a hierarchical network of blind-ended lymphatic capillaries and collecting lymphatic vessels, both lined by lymphatic endothelial cells (LECs). The low hydrostatic pressure in lymphatic capillaries, their loose intercellular junctions, and attachment to the surrounding extracellular matrix (ECM) permit passage of extravasated blood plasma from the interstitium into the lumen of the lymphatic capillaries. It is generally thought that interstitial fluid accumulation leads to a swelling of the ECM, to which the LECs of lymphatic capillaries adhere, for example via anchoring filaments. As a result, LECs are pulled away from the vascular lumen, the junctions open, and fluid enters the lymphatic vasculature. The collecting lymphatic vessels then gather the plasma fluid from the capillaries and carry it through the lymph nodes to the blood circulation. The collecting vessels contain intraluminal bicuspid valves that prevent fluid backflow, and are embraced by smooth muscle cells that contribute to fluid transport. Although the lymphatic vessels are regular subject to mechanical strain, our knowledge of its influence on lymphatic development and pathologies is scarce. Here, we discuss the mechanical forces and molecular mechanisms regulating lymphatic vascular growth and maturation in the developing mouse embryo. We also consider how the lymphatic vasculature might be affected by similar mechanomechanisms in two pathological processes, namely cancer cell dissemination and secondary lymphedema. © 2013 Springer Basel.

Planas-Paz L.,Heinrich Heine University Dusseldorf | Lammert E.,Heinrich Heine University Dusseldorf | Lammert E.,Paul Langerhans Group for Beta Cell Biology
Advances in Anatomy Embryology and Cell Biology | Year: 2014

The lymphatic vasculature is responsible for fluid homeostasis, transport of immune cells, inflammatory molecules, and dietary lipids. It is composed of a network of lymphatic capillaries that drain into collecting lymphatic vessels and ultimately bring fluid back to the blood circulation. Lymphatic endothelial cells (LECs) that line lymphatic capillaries present loose overlapping intercellular junctions and anchoring filaments that support fluid drainage. When interstitial fluid accumulates within tissues, the extracellular matrix (ECM) swells and pulls the anchoring filaments. This results in opening of the LEC junctions and permits interstitial fluid uptake. The absorbed fluid is then transported within collecting lymphatic vessels, which exhibit intraluminal valves that prevent lymph backflow and smooth muscle cells that sequentially contract to propel lymph. Mechanotransduction involves translation of mechanical stimuli into biological responses. LECs have been shown to sense and respond to changes in ECM stiffness, fluid pressure-induced cell stretch, and fluid flow-induced shear stress. How these signals influence LEC function and lymphatic vessel growth can be investigated by using different mechanotransduction assays in vitro and to some extent in vivo. In this chapter, we will focus on the mechanical forces that regulate lymphatic vessel expansion during embryonic development and possibly secondary lymphedema. In mouse embryos, it has been recently shown that the amount of interstitial fluid determines the extent of lymphatic vessel expansion via a mechanosensory complex formed by β1 integrin and vascular endothelial growth factor receptor-3 (VEGFR3). This model might as well apply to secondary lymphedema. © Springer-Verlag Wien 2014.

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