Publications

Oxidative phosphorylation in mitochondria is responsible for 90% of ATP synthesis in most cells. This essential housekeeping function is mediated by nuclear and mitochondrial genes encoding subunits of complex I to V of the respiratory chain. Although complex IV is the best studied of these complexes, the exact function of the striated muscle-specific subunit COX6A2 is still poorly understood. In this study, we show that Cox6a2-deficient mice are protected against high-fat diet-induced obesity, insulin resistance and glucose intolerance. This phenotype results from elevated energy expenditure and a skeletal muscle fiber type switch towards more oxidative fibers. At the molecular level we observe increased formation of reactive oxygen species, constitutive activation of AMP-activated protein kinase, and enhanced expression of uncoupling proteins. Our data indicate that COX6A2 is a regulator of respiratory uncoupling in muscle and we demonstrate that a novel and direct link exists between muscle respiratory chain activity and diet-induced obesity/insulin resistance.

The use of monoclonal antibodies targeting PlGF could thus offer a potential systemic treatment for patients who suffer from primary liver tumours.

Hepatocyte death is an important contributing factor in a number of diseases of the liver. PHD1 confers hypoxic sensitivity upon transcription factors including the hypoxia inducible factor (HIF) and nuclear factor-kappaB (NF-κB). Reduced PHD1 activity is linked to decreased apoptosis. Here, we investigated the underlying mechanism(s) in hepatocytes. Basal NF-κB activity was elevated in PHD1(-/-) hepatocytes compared to wild type controls. ChIP-seq analysis confirmed enhanced binding of NF-κB to chromatin in regions proximal to the promoters of genes involved in the regulation of apoptosis. Inhibition of NF-κB (but not knock-out of HIF-1 or HIF-2) reversed the anti-apoptotic effects of pharmacologic hydroxylase inhibition. We hypothesize that PHD1 inhibition leads to altered expression of NF-κB-dependent genes resulting in reduced apoptosis. This study provides new information relating to the possible mechanism of therapeutic action of hydroxylase inhibitors that has been reported in pre-clinical models of intestinal and hepatic disease.

<div>Abstract<p>Treatment of bone metastases is largely symptomatic and is still an unmet medical need. Current therapies mainly target the late phase of tumor-induced osteoclast activation and hereby inhibit further metastatic growth. This treatment method is, however, less effective in preventing initial tumor engraftment, a process that is supposed to depend on the bone microenvironment. We explored whether bone-derived placental growth factor (PlGF), a homologue of vascular endothelial growth factor-A, regulates osteolytic metastasis. Osteogenic cells secrete PlGF, the expression of which is enhanced by bone-metastasizing breast tumor cells. Selective neutralization of host-derived PlGF by anti-mouse PlGF (αPlGF) reduced the incidence, number, and size of bone metastases, and preserved bone mass. αPlGF did not affect metastatic tumor angiogenesis but inhibited osteoclast formation by preventing the upregulation of the osteoclastogenic cytokine receptor activator of NF-κB ligand in osteogenic cells, as well as by blocking the autocrine osteoclastogenic activity of PlGF. αPlGF also reduced the engraftment of tumor cells in the bone and inhibited their interaction with matrix components in the metastatic niche. αPlGF therefore inhibits not only the progression of metastasis but also the settlement of tumor in the bone. These findings identify novel properties of PlGF and suggest that αPlGF might offer opportunities for adjuvant therapy of bone metastasis. Cancer Res; 70(16); 6537–47. ©2010 AACR.</p></div>

Abstract Background Plasmin system components are upregulated after partial hepatectomy, but their contribution to surgery-induced hepatic angiogenesis and regeneration is unclear. Liver regeneration and angiogenesis after partial hepatectomy were examined in mice lacking plasminogen or urokinase plasminogen activator (uPA). Methods Mice with a single-gene deletion of plasminogen or uPA were subjected to 70 per cent partial hepatectomy. Liver regeneration was measured as relative liver weight and cell proliferation index. Angiogenesis was quantified by determining hepatic microvessel density after staining for sinusoidal endothelial cells. Results The liver remnant weight was significantly reduced in mice lacking plasminogen or uPA compared with that in wild-type mice on days 2 and 7 after partial hepatectomy. This correlated with impaired cell proliferation. In wild-type mice, regeneration was accompanied by a significant increase in microvessel density after hepatectomy; this increase was impaired in plasminogen-deficient mice. Conclusion Plasminogen and uPA are essential for optimal liver regeneration. In addition, plasminogen appears to be a major determinant in regeneration-associated hepatic angiogenesis.

<p>Overview of cancer-associated PPP2R4 exome mutations found in COSMIC and cBioportal cancer databases.</p>

V ascular dysfunction is causally contributing to many dis- eases, including but not limited to cardiovascular disease, which is still the leading cause of death in the Western world.The endothelium that lines the inner wall of the blood vessels plays a critical role in the pathobiology of these illnesses.Particularly after ischemia or injury, the growth of new blood vessels, driven by endothelial expansion, is essential to maintain oxygen supply to the ischemic or injured tissue.Recent studies additionally suggest that the endothelium acts as a paracrine source for signals that determine tissue regeneration versus fibrosis after injury.Excessive vascularization, however, might also be unwanted, as in the case of cancer, neovascular eye diseases including diabetic retinopathy, atheroma growth, or the expansion of vasa vasorum, which leads to adverse vessel wall remodeling.Neovascularization is a tightly regulated and essential process that results in the formation of new blood vessels.Specific types of neovascularization include angiogenesis, the formation of new capillaries from existing capillaries, and arteriogenesis, the formation of new arteries from preexisting collaterals or de novo.Although endothelial cells (ECs) certainly are essential for both processes, the formation of functionally active vessels requires a complex molecular cross-talk of ECs with perivascular cells such as pericytes, smooth muscle cells, and macrophages.Simple in vitro models are best suited to examine specific aspects of particular processes involved in angiogenesis such as the biochemical interactions that regulate EC proliferation, motility, and apoptosis or lumen formation.However, in vivo models are required to understand the complex cellular interactions that enable the generation of functionally active and hierarchical blood vessel networks capable of providing an appropriate blood supply and paracrine stimuli to organs.In addition, the development of therapeutic strategies to either promote or inhibit vessel growth depends on reproducible measures and end points in experimental models that are relevant for the treatment of human diseases.Accordingly, the selection of an appropriate experimental model is critical to study specific aspects of the molecular and cellular mechanisms that are of physiological or pathological relevance.This scientific statement summarizes in vitro assays and in vivo models suitable for gaining insights into the basic mechanisms of vessel growth and provides an overview of models that are particularly useful for clinical translation. In Vitro AssaysConsiderable progress has been made over the past 20 years in the development of in vitro strategies to investigate the complex processes of vascular morphogenesis and maturation events in