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Dr Derek Lang

Reader

School of Medicine

Email:
langd@cardiff.ac.uk
Telephone:
+44 (0)29 2074 2058
Location:
Geraint Evans Heart Research
Media commentator

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.

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Areas of expertise