Here are just a few examples from the range of internationally leading translational research within CVS.
11b-HSD1 in metabolic syndrome
The metabolic syndrome comprises major cardiovascular risk factors including obesity, type 2 diabetes, dyslipidaemia and hypertension and can be induced by excessive action of steroid hormones such as cortisol. CVS researchers demonstrated in animals and humans that 11b-HSD1 amplifies cortisol action in liver, adipose tissue and brain; that exaggerated 11b-HSD1 activity occurs in metabolic syndrome; and that reducing 11b-HSD1 protects against metabolic syndrome, atherogenesis and tissue damage following ischaemia. This is now being exploited, including in the CVS drug discovery group, to provide novel therapy to prevent cardiovascular disease.
11b-HSD2 in salt-sensitive hypertension.
CVS researchers generated a novel mouse model of salt-sensitive hypertension caused by impaired inactivation of glucocorticoids by 11b-HSD2, mimicking the human syndrome of apparent mineralocorticoid excess and, by crossing these mice with ApoE-/- mice, produced a model of accelerated atherosclerosis without the need for high cholesterol diet.
Renin secretion and ‘malignant’ hypertension.
The renin-angiotensin-aldosterone system is a crucial mediator of cardiovascular control and target for current therapies. CVS researchers have pioneered transgenesis in rats to demonstrate the consequences of excessive renin secretion, including providing models of accelerated phase (or ‘malignant’) hypertension and its inflammatory consequences in the kidney.
Early life ‘programming’ of cardiovascular risk.
To explain observations that low birthweight predicts adult cardiovascular and metabolic disorders, researchers in CVS developed the ‘glucocorticoid’ hypothesis of fetal programming. Exploring this paradigm in animal models and humans led to identification of pathways susceptible to programming and evidence for their epigenetic regulation, providing fundamental insights into the origins of cardiovascular risk.
Endothelin receptors in pulmonary and systemic hypertension.
Several endothelium-derived mediators are investigated within CVS. Work in CVS was first to show the role of the endothelin receptors (ET-A and ET-B) in regulation of vascular tone and blood pressure in humans and the clinical potential of ET-A receptor antagonism in pulmonary hypertension. More recently, receptor antagonists have been used to show that ET-1 contributes to hypertension, renal haemodynamics and proteinuria in chronic kidney disease, which carries very high cardiovascular risk.
Environmental pollution and vascular biology.
Endothelial cells are also responsible for release of endogenous fibrinolytics. In pioneering studies, CVS researchers have studied regulation of endogenous fibrinolysis in the peripheral and coronary circulation, eg by smoking and by nanoparticles found in diesel exhaust. They also showed that diesel exposure promotes myocardial ischemia and inhibits endogenous fibrinolytic capacity in patients with stable coronary heart disease.
Novel pathways in cell biology.
Studies in Drosophila identified novel roles for the RFC4 (Replication Factor C, subunit 4) and ORC2 (Origin Recognition Complex, subunit 2) proteins in mitotic chromosome condensation and segregation; led to the identification and genetic and biochemical characterization of the condensin and cohesin complex subunits (e.g. SMC2, SMC4, CAP-D2, Rad21); and identified a novel metalloprotease (invadolysin) that is conserved in metazoa, plays crucial roles in cell division and cell migration, and is a component of the surface of lipid droplets, the first metalloprotease to be identified on this subcellular organelle.
Control of circadian and neuroendocrine rhythms.
Cardiovascular ‘events’ (heart attack, stroke, etc) occur more frequently in the morning. CVS researchers showed that rhythmic activity of the “master clock” driving circadian rhythms, located in the suprachiasmatic nucleus (SCN) of the hypothalamus, is dependent upon signalling between SCN neurons mediated by the neuropeptide vasoactive intestinal peptide (VIP). Disruption of neuroendocrine rhythmicity appears also to underlie the associations between elevated morning plasma cortisol, metabolic syndrome and cardiovascular risk, demonstrated in epidemiological studies led by CVS researchers.
Determinants of outcome from acute coronary syndrome.
CVS is also active in direct delivery of improved clinical management for patients with cardiovascular disease. The GRACE registry comprises a large cohort of patients with carefully defined Acute Coronary Syndrome, across 14 countries. It provided robust risk scores for death, myocardial infarction and major complications that have been adopted widely in clinical practice. CVS researchers are also key players in substantial multi-centre intervention studies, eg the RITA-3 study which showed the benefits of early angiography and intervention following myocardial infarction.