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Dr Andrew S Cowburn

Dr Andrew S Cowburn

Senior Research Associate


Office Phone: +44 (0) 1223 333882

Research Interests

Physiology

The skin plays an essential role, mediated in part by its remarkable vascular plasticity, in adaptation to environmental stimuli. When established, primary HTN is characterized by increased peripheral vascular resistance (PVR). Increased PVR includes altered vascular resistance in the skin, evident at an early stage in primary HTN. Research Focus: To determine the factors relevant to the regulation of PVR in HTN, we chose the epidermis as a target tissue for manipulation of a key element in vascular function, the hypoxia-inducible transcription factor (HIF). The elimination of one of the two key HIF isoforms, HIF-1a, in the epidermis did not change skin vascular density, but did increase systemic arterial pressure, with a concomitant increase in cardiac fibrosis and the expression of markers of cardiac hypertensive stress in the mutant animals. Surprisingly, loss of the HIF-2a isoform had the opposite effect, causing a reduction in blood pressure, i.e., systemic hypotension. These aggravating and ameliorating effects of HIF-1a and HIF-2a were seen in experimental HTN models, and were correlated with differential regulation of nitric oxide (NO) by the two isoforms. To determine the clinical relevance of these observations, skin biopsies from human subjects, including untreated hypertensives, were assayed, and revealed a significant linear correlation of decreased skin HIF-1a expression with increased systolic pressure. Further, although the two isoforms were coordinately controlled in normotensive humans, this co-regulation of the two HIF-a isoforms was lost in skin from hypertensive subjects. These data demonstrate that HIF-a isoform balance in the epidermis regulates systemic arterial pressure, and suggests that altered regulation of the two HIF-a isoforms could underlie tissue changes leading to increased PVR and primary HTN.

Inflammation

Neutrophil apoptosis is essential for the resolution of inflammation but is delayed by several inflammatory mediators. In such terminally differentiated cells it was uncertain whether these agents could inhibit apoptosis through transcriptional regulation of anti-death (Bcl-X(L), Mcl-1, Bcl2A1) or BH3-only (Bim, Bid, Puma) Bcl2-family proteins. Research focus: To determine the role of PI3-kinase/AKT, NF-?B and MAPK signalling pathways regulating neutrophil apoptosis. We described the differential expression and phosphorylation status of Bcl2-like proteins and their subsequent interactions, which may correspond to the cells fate. Previously I have shown that GM-CSF and TNF? mediated survival of human neutrophils is associated with a PI3-kinase-dependent phosphorylation of Bad at Ser-112 and Ser136. The phosphorylation of Bad promoted its redistribution to the cytosolic compartment and thus preventing dimerization with anti-apoptotic proteins.

We have also shown that GM-CSF and TNF-α increase and/or maintain mRNA levels for the pro-apoptotic BH3-only protein Bid and that GM-CSF has a similar NF-κB-dependent effect on Bim transcription and BimEL expression. The in-vivo relevance of these findings was indicated by demonstrating that GM-CSF is the dominant neutrophil survival factor in lung lavage from patients with ventilator-associated pneumonia, confirming an increase in lung neutrophil Bim mRNA. Interestingly, GM-CSF also caused mitochondrial relocation of Bim and a switch in phenotype to a cell that displays accelerated caspase-9-dependent apoptosis. This demonstrated the capacity of neutrophil survival agents to induce a paradoxical increase in the pro-apoptotic proteins Bid and Bim and suggested that this may function to facilitate rapid apoptosis at the termination of the inflammatory cycle.

Above: Thermal image analysis of mouse skin. (Right image) Wild-type mice with normal skin temperature (Top left) Keratinocyte deletion of VHL leads to the un-checked expression of hypoxia inducible factors leading to epidermal vasodilation. Due to the massive loss of core temperature the mice display hypothermic tendencies. (lower left) the hyperthermic mice recover once fed a high-fat diet.

Above: Pathogen induced deployment of neutrophil extracellular traps.