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Research in the Triggle Laboratory focuses on the role of the endothelium in the regulation of vascular tone in normal and pathophysiological states. The current emphasis is directed to obesity and diabetes where changes in adipose tissue function and the diabetic milieu are associated with significant elevations in cardiovascular-related morbidity and mortality.
An overview of Dr. Triggle’s contributions to our understanding of smooth muscle and cardiovascular physiology and pharmacology is provided by Google Scholar revealing > 5900 citations and an h-index of 45:
Dr. Triggle is involved in research collaborations both locally in Qatar with Dr. Hong Ding as well as internationally with Professors Kim Dora and Christopher Garland, The University of Oxford; Professors Paul Vanhoutte and Aimin Xu, The University of Hong Kong; and Professor Morley Hollenberg, The University of Calgary.
The endothelium is a single layer of cells that line the lumen of all blood vessels and communication between endothelial and vascular smooth muscle cells plays a critical role in the regulation of blood flow and blood pressure. The importance of the endothelium in the regulation of vascular function first became apparent as a result of Robert Furchgott’s discovery of the obligatory role played by the endothelium in mediating endothelium-dependent vasodilatation (EDV) effect of acetylcholine that resulted in a 1980 publication in Nature. We now know that the endothelium-derived mediator that was described in the 1980 publication is nitric oxide (NO) that is generated by the enzyme endothelial nitric oxide synthase (eNOS) from the amino acid, L-arginine. However, it is not just NO that is involved in endothelium-dependent regulation of vascular tone as we now know that, particularly in the microcirculation, low electrical resistance myoendothelial gap junctions (MEGJs), play a very important role in the regulation of vasomotion and blood flow. MEGJs are most likely the conduits for endothelium-dependent hyperpolarization (EDH) that is critical for the regulation of vasomotion and blood flow. Furthermore, in addition to NO other chemical mediators such as hydrogen peroxide and the cytochrome P450 metabolites of arachidonic acid, epoxyeicosatrienoic acids (EETs) and, in some vascular beds, are considered putative candidate chemical mediators, or "factors" endothelium-derived hyperpolarizing factor, or EDHF) for mediating EDH:
Triggle et al., Canadian J. Physiology & Pharmacology, 90, 713-738; 2012.
Proteinase-activated receptors: A longstanding collaboration with Professor Hollenberg involves the role of proteinase-activated receptors (PARs) in the regulation of vascular function and has resulted in a number of important contributions that, for instance, links to activation of PAR2 receptors to non-nitric oxide/non-prostacyclin mediated EDV. Current studies are underway to elucidate how PAR1- & PAR2-mediated signalling is affected by diabetes.
Hyperglycaemia & endothelial dysfunction: Diabetes results in endothelial dysfunction and a very early indicator of the development of vascular disease is a reduction in the endothelium-dependent vasodilation response to acetylcholine – a reduced EDV. Our research has demonstrated the link between high levels of glucose (hyperglycaemia), the reduction of the co-factor, tetrahydrobiopterin (BH4) and the uncoupling of eNOS from the NO-generating dimer to a superoxide generating monomeric eNOS.
Ding, H., Aljofan, M., & Triggle, CR. Oxidative stress and increased eNOS and NADPH oxidase expression in cell cultures of mouse microvessel endothelial cells exposed to high glucose. J. Cell Physiol. 212, 682-689; 2007.
An NPRP-funded project with Professors Dora & Garland at the University of Oxford focusing on the cellular mechanisms whereby hyperglycaemia alters endothelial function and conducted vasomotion in the microcirculation. In humans a sudden increase in blood glucose levels results in a reduction in flow-mediated vasodilatation indicating that hyperglycaemia results in a rapid onset of endothelial dysfunction. The primary objective of the collaboration is to understand the cellular mechanisms that link hyperglycaemia to the development of vascular disease.
Another area of interest is the link between obesity and diabetes and the elevated risk of vascular disease. An emerging area of interest relates to the perivascular adipose tissue (PVAT) that surrounds blood vessels as it now recognized that PVAT has important effects on vascular function. The PVAT is the source of numerous bioactive factors (adipokines) that can both positively and negatively modulate vascular function and because there is no fascia barrier between PVAT and the adventitia such PVAT-derived factors can directly affect vascular function:
Li et al., British J. Pharmacology, 164, 1990-2002; 2011.,
In collaboration with Professors Xu & Vanhoutte at the University of Hong Kong studies regarding the role of brown and white adipose tissue in the regulation of vascular function in normal and pathophysiological states such as obesity.
Metformin and vascular disease: In collaboration with Dr. Ding’s research group we have also explored the question of whether metformin, the first choice anti-diabetic drug for the treatment of type 2 diabetes, has a direct protective action against the effects of hyperglycaemia on endothelial function. Our data, published in a series of papers during 2014-2015 indicates that metformin, at therapeutically relevant concentrations, has both a rapid and a longer term sustained effects on endothelial function that are mediated via promoting phosphorylation of eNOS at serine 1177 and also via the deacetylase, sirtuin 1. Sirtuin 1 is the protein product of SIRT1 that is sometimes referred to as the “anti-ageing gene” and that metformin helps maintain SIRT1 expression provides a molecular explanation for the clinical data suggesting a reduction in diabetes-related increases in cardiovascular morbidity and mortality.
- Gnanapragasam Arunachalam, Samson Mathews Samuel, Isra Marei, Hong Ding and Chris R. Triggle Metformin modulates hyperglycaemia-induced endothelial senescence and apoptosis through SIRT1. British J Pharmacology, 2014; 171(2):523-535.
- Ghosh S, Lakhsmanan AP, Mu Ji Hwang Mu J, Kubba H, Ahmed Mushannen A, Triggle CR, Ding H. Metformin improves endothelial function in aortic tissue and microvascular endothelial cells subjected to diabetic hyperglycaemic conditions. Biochemical Pharmacology. 2015; 98(3):412-421.
Furthermore, hyperglycaemia results in changes in the expression in endothelial cells of a number of microRNAs and, of particular interest, is microRNA34a that is also known to modulate the expression of SIRT1. Metformin reduces microRNA34a expression suggesting that the vascular protective effects of metformin involve the modulation of microRNA expression.
Our findings also provides a scientific basis for the statement attributed to Rudolf Altschul, Professor of Anatomy, University of Saskatchewan, Canada and appearing in his monograph 'Endothelium’ (1954):
Metformin & cancer: In the past 10 years considerable interest has been directed towards the potential contribution of metformin and the reduction in the risk of cancer in patients with diabetes. Based primarily on retrospective analysis and observational studies patients treated with metformin show a lower incidence of a number of cancers. Although the interpretation of such data is quite controversial numerous studies have pursued in vitro protocols with a variety of cancer cell lines and demonstrated anti-proliferative effects of metformin, albeit at very high concentrations. That the majority of such studies have used millimolar concentrations of metformin raises the possibility that what is being reported is a “Paracelsus effect”. Studies are underway to better understand how metformin affects pro-survival and pro-apoptotic pathways in both endothelial and cancer cell lines with a particular focus on the effects of glucose concentration as well as the expression of organic cation transporters.
See: Triggle CR, Ding H. Metformin is not just an antihyperglycaemic drug but also has protective effects on the vascular endothelium Acta Physiol (Oxf). In press.