Yr Athro Derek Lang
Cadeirydd Personol
- Sylwebydd y cyfryngau
Trosolwyg
Major Research Interests:
The foundations of my research are based in the field of endothelial and vascular smooth muscle cell biology. With a particular interested in the mechanisms that underlie endothelial/vascular dysfunction in various cardiovascular disease states. Recent years have seen significant developments in the role(s) of folic acid in improving endothelial function thanks to continued funding from the BHF. Further investigations (in collaboration with Dr AS Williams, Cardiff Institute of Infection & Immunity) into the mechanisms underlying vascular dysfunction in rheumatoid arthritis are also well supported by the BHF and are ongoing.
Folic acid
Whether folic acid has a role in improving cardiovascular health remains very controversial. Indeed many studies suggest that it has no beneficial effect. However, our firm belief that it does is supported by significant previous publications from our group. We have observed a direct role for this vitamin in activating endothelial cell nitric oxide synthase (eNOS) (Taylor et al. Eur J Pharmacol, 2013;714:193-201). This involves increased NO release, eNOS dimerisation (Moat et al. Eur J Clin Invest. 2006;36:850-859), PI3K and PKA-mediated eNOS phosphorylation at serines 635 and 1179, as well as alterations in the interaction of eNOS with the regulatory proteins caveolin-1 and HSP-90 (Taylor et al. Eur J Pharmacol, 2013;714:193-201). More recently our data shows folic acid to promote eNOS activation via CaMKII-mediated phosphorylation in the absence of increased eNOS/CaM association. Activation is accompanied by increased translocation of eNOS to cellular membranes (Taylor et al. Circulation, 2001;124:21). Importantly these data would implicate folic acid in the optimisation of normal endothelial function prior to an initial cardiovascular event.
Vascular dysfunction in rheumatoid arthritis
Evidence for a link between rheumatoid arthritis (RA) and cardiovascular disease (CVD) is overwhelming and the large RA-associated inflammatory burden is thought to be responsible for the development of such distal pathologies; inflammatory mediators characteristic of RA cause injury to the endothelium ultimately resulting in endothelial dysfunction, a precursor to CVD. Our recent publication (Reynolds et al. Br J Pharmacol, 2012;167:505-514) demonstrated contractile dysfunction (evidenced by a reduced capability to constrict to specific mediators K+ and the agonist 5-hydroxytryptamine compared to normal control vessels) in the face of arthritis development. Interestingly, and in contrast to many studies in the literature, endothelial function appeared unchanged throughout disease. Subsequent investigations ruled out a role for increased production of nitric oxide and prostacyclin in this pathology. Conversely aortic (and also paw and plasma) levels of the matrixmetalloprotein MMP-9 were shown to associate with increasing contractile dysfunction.
These findings suggest that systemic and vascular wall levels of MMP-9, related to inflammation at the joint site, may play a prominent role in the development of vascular dysfunction. Importantly identification of the earliest changes in vascular function following the initial onset of RA, and the pathological mechanisms therein, may result in a re-evaluation of current treatments or indeed the development of new therapies.
Further work
Under the auspices of another BHF PhD studentship (Red blood-cell induced vasorelaxation – a role for oxygen?), an important existing collaboration with Dr PE James (Cardiff Institute of Molecular & Experimental Medicine) has been extended. A significant manuscript resulting from this work has been published recently (Dada J et al. Plos One, 2013;8:e57162). The data presented confirms that in hypoxic conditions molecular oxygen can be a direct and important mediator of vasodilation through an increase in cGMP production. In the wider context, these observations are key to understanding the relative roles of oxygen versus nitric oxide-induced soluble guanylate cyclase activation.
Cyhoeddiad
2021
- Davies, R. et al. 2021. The role of interleukin-6 trans-signalling on cardiovascular dysfunction in inflammatory arthritis. Rheumatology 60(6), pp. 2852-2861., article number: keaa725. (10.1093/rheumatology/keaa725)
2016
- Williams, J., Wang, E. C. Y., Lang, D. and Williams, A. S. 2016. Characterisation of Death Receptor 3 dependent aortic changes during inflammatory arthritis. Pharmacology Research & Perspectives 4(4), article number: e0024. (10.1002/prp2.240)
2013
- Taylor, S. Y., Dixon, H. M., Yoganayagam, S., Price, N. and Lang, D. 2013. Folic acid modulates eNOS activity via effects on posttranslational modifications and protein–protein interactions. European Journal of Pharmacology 714(1-3), pp. 193-201. (10.1016/j.ejphar.2013.05.026)
- Dada, J., Pinder, A. G., Lang, D. and James, P. E. 2013. Oxygen mediates vascular smooth muscle relaxation in hypoxia. PLoS ONE 8(2), article number: e57162. (10.1371/journal.pone.0057162)
2012
- Reynolds, S. L. et al. 2012. Contractile, but not endothelial, dysfunction in early inflammatory arthritis: a possible role for matrix metalloproteinase-9. British Journal of Pharmacology 167(3), pp. 505-514. (10.1111/j.1476-5381.2012.01988.x)
2011
- Bundhoo, S. et al. 2011. Direct vasoactive properties of thienopyridine-derived nitrosothiols. Journal of Cardiovascular Pharmacology 58(5), pp. 550-558. (10.1097/FJC.0b013e31822f578c)
2010
- Caddy, J. et al. 2010. Rosiglitazone induces the unfolded protein response, but has no significant effect on cell viability, in monocytic and vascular smooth muscle cells. Biochemical and Biophysical Research Communications 400(4), pp. 689-695. (10.1016/j.bbrc.2010.08.129)
- Matthews, I. P., Henderson, K. A., Gregory, C. J., Palmer, S. R. and Lang, D. 2010. Effects of emissions from different type of residential heating upon cyclic guanosine monophosphate (cGMP) in blood platelets of residents. Biomarkers 15(1), pp. 86-93. (10.3109/13547500903311894)
2009
- Lang, D. and James, P. E. 2009. Free nitric oxide in spent CAPD fluid: a leap of faith?. Peritoneal Dialysis International 29(5), pp. 505-507.
2008
- Caddy, J. et al. 2008. Rosiglitazone transiently disturbs calcium homeostasis in monocytic cells. Biochemical and Biophysical Research Communications 366(1), pp. 149-155. (10.1016/j.bbrc.2007.11.095)
2006
- Clarke, Z. L., Moat, S. J., Miller, A. L., Randall, M. D., Lewis, M. J. and Lang, D. 2006. Differential effects of low and high dose folic acid on endothelial dysfunction in a murine model of mild hyperhomocysteinaemia. European Journal of Pharmacology 551(1-3), pp. 92-97. (10.1016/j.ejphar.2006.08.085)
- Moat, S. J. et al. 2006. High- but not low-dose folic acid improves endothelial function in coronary artery disease. European Journal Of Clinical Investigation 36(12), pp. 850-859. (10.1111/j.1365-2362.2006.01739.x)
- Moat, S. J., Clarke, Z. L., Madhavan, A. K., Lewis, M. J. and Lang, D. 2006. Folic acid reverses endothelial dysfunction induced by inhibition of tetrahydrobiopterin biosynthesis. European Journal of Pharmacology 530(3), pp. 250-258. (10.1016/j.ejphar.2005.11.047)
2004
- Van Den Berg, C. W., Taylor, K. E. and Lang, D. 2004. C-reactive protein-induced in vitro vasorelaxation is an artefact caused by the presence of sodium azide in commercial preparations. Arteriosclerosis Thrombosis and Vascular Biology 24(10), pp. e168-171. (10.1161/01.ATV.0000142807.92781.d9)
- James, P. E., Lang, D., Tufnell-Barret, T., Milsom, A. B. and Frenneaux, M. P. 2004. Vasorelaxation by red blood cells and impairment in diabetes: reduced nitric oxide and oxygen delivery by glycated hemoglobin. Circulation Research 94(7), pp. 976-983. (10.1161/01.RES.0000122044.21787.01)
2001
- Doshi, S. N. et al. 2001. Folate improves endothelial function in coronary artery disease: an effect mediated by reduction of intracellular superoxide?. Arteriosclerosis Thrombosis and Vascular Biology 21(7), pp. 1196-1202. (10.1161/hq0701.092000)
1993
- Williams, J., Lang, D., Warden-Smith, J. and Lewis, M. J. 1993. Plasma L-arginine levels in a rabbit model of hypercholesterolaemia. Biochemical Pharmacology 46(11), pp. 2097-2099. (10.1016/0006-2952(93)90653-E)
- Lang, D., Warden-Smith, J. and Lewis, M. J. 1993. Induction of a calcium-independent NO synthase by hypercholesterolaemia in the rabbit. British Journal of Pharmacology 108(2), pp. 290-292.
1990
- Warden-Smith, J. and Lang, D. 1990. Release of endothelium-derived relaxing factor from pig cultured aortic endothelial cells, as assessed by changes in endothelial cell cyclic GMP content, is inhibited by a phorbol ester. British Journal of Pharmacology 99(3), pp. 565-71.
Articles
- Davies, R. et al. 2021. The role of interleukin-6 trans-signalling on cardiovascular dysfunction in inflammatory arthritis. Rheumatology 60(6), pp. 2852-2861., article number: keaa725. (10.1093/rheumatology/keaa725)
- Williams, J., Wang, E. C. Y., Lang, D. and Williams, A. S. 2016. Characterisation of Death Receptor 3 dependent aortic changes during inflammatory arthritis. Pharmacology Research & Perspectives 4(4), article number: e0024. (10.1002/prp2.240)
- Taylor, S. Y., Dixon, H. M., Yoganayagam, S., Price, N. and Lang, D. 2013. Folic acid modulates eNOS activity via effects on posttranslational modifications and protein–protein interactions. European Journal of Pharmacology 714(1-3), pp. 193-201. (10.1016/j.ejphar.2013.05.026)
- Dada, J., Pinder, A. G., Lang, D. and James, P. E. 2013. Oxygen mediates vascular smooth muscle relaxation in hypoxia. PLoS ONE 8(2), article number: e57162. (10.1371/journal.pone.0057162)
- Reynolds, S. L. et al. 2012. Contractile, but not endothelial, dysfunction in early inflammatory arthritis: a possible role for matrix metalloproteinase-9. British Journal of Pharmacology 167(3), pp. 505-514. (10.1111/j.1476-5381.2012.01988.x)
- Bundhoo, S. et al. 2011. Direct vasoactive properties of thienopyridine-derived nitrosothiols. Journal of Cardiovascular Pharmacology 58(5), pp. 550-558. (10.1097/FJC.0b013e31822f578c)
- Caddy, J. et al. 2010. Rosiglitazone induces the unfolded protein response, but has no significant effect on cell viability, in monocytic and vascular smooth muscle cells. Biochemical and Biophysical Research Communications 400(4), pp. 689-695. (10.1016/j.bbrc.2010.08.129)
- Matthews, I. P., Henderson, K. A., Gregory, C. J., Palmer, S. R. and Lang, D. 2010. Effects of emissions from different type of residential heating upon cyclic guanosine monophosphate (cGMP) in blood platelets of residents. Biomarkers 15(1), pp. 86-93. (10.3109/13547500903311894)
- Lang, D. and James, P. E. 2009. Free nitric oxide in spent CAPD fluid: a leap of faith?. Peritoneal Dialysis International 29(5), pp. 505-507.
- Caddy, J. et al. 2008. Rosiglitazone transiently disturbs calcium homeostasis in monocytic cells. Biochemical and Biophysical Research Communications 366(1), pp. 149-155. (10.1016/j.bbrc.2007.11.095)
- Clarke, Z. L., Moat, S. J., Miller, A. L., Randall, M. D., Lewis, M. J. and Lang, D. 2006. Differential effects of low and high dose folic acid on endothelial dysfunction in a murine model of mild hyperhomocysteinaemia. European Journal of Pharmacology 551(1-3), pp. 92-97. (10.1016/j.ejphar.2006.08.085)
- Moat, S. J. et al. 2006. High- but not low-dose folic acid improves endothelial function in coronary artery disease. European Journal Of Clinical Investigation 36(12), pp. 850-859. (10.1111/j.1365-2362.2006.01739.x)
- Moat, S. J., Clarke, Z. L., Madhavan, A. K., Lewis, M. J. and Lang, D. 2006. Folic acid reverses endothelial dysfunction induced by inhibition of tetrahydrobiopterin biosynthesis. European Journal of Pharmacology 530(3), pp. 250-258. (10.1016/j.ejphar.2005.11.047)
- Van Den Berg, C. W., Taylor, K. E. and Lang, D. 2004. C-reactive protein-induced in vitro vasorelaxation is an artefact caused by the presence of sodium azide in commercial preparations. Arteriosclerosis Thrombosis and Vascular Biology 24(10), pp. e168-171. (10.1161/01.ATV.0000142807.92781.d9)
- James, P. E., Lang, D., Tufnell-Barret, T., Milsom, A. B. and Frenneaux, M. P. 2004. Vasorelaxation by red blood cells and impairment in diabetes: reduced nitric oxide and oxygen delivery by glycated hemoglobin. Circulation Research 94(7), pp. 976-983. (10.1161/01.RES.0000122044.21787.01)
- Doshi, S. N. et al. 2001. Folate improves endothelial function in coronary artery disease: an effect mediated by reduction of intracellular superoxide?. Arteriosclerosis Thrombosis and Vascular Biology 21(7), pp. 1196-1202. (10.1161/hq0701.092000)
- Williams, J., Lang, D., Warden-Smith, J. and Lewis, M. J. 1993. Plasma L-arginine levels in a rabbit model of hypercholesterolaemia. Biochemical Pharmacology 46(11), pp. 2097-2099. (10.1016/0006-2952(93)90653-E)
- Lang, D., Warden-Smith, J. and Lewis, M. J. 1993. Induction of a calcium-independent NO synthase by hypercholesterolaemia in the rabbit. British Journal of Pharmacology 108(2), pp. 290-292.
- Warden-Smith, J. and Lang, D. 1990. Release of endothelium-derived relaxing factor from pig cultured aortic endothelial cells, as assessed by changes in endothelial cell cyclic GMP content, is inhibited by a phorbol ester. British Journal of Pharmacology 99(3), pp. 565-71.