Intracellular signalling

Dr Paul Evans, Head of Group 

Biomechanical forces and vascular physiology

We are studying the effects of shear stress (a mechanical force exerted by flowing blood) on pro-inflammatory and pro-apoptotic signalling pathways in vascular endothelial cells (EC). This subject is relevant to vascular injury and atherosclerosis which develop predominantly at branches and bends in the arterial tree that are exposed to low or oscillatory shear stress, whereas regions of arteries that are exposed to high shear stress are protected. Our group wishes to understand the molecular mechanisms that govern the spatial distribution of vascular inflammation and atherosclerosis in relation to local hemodynamics. Our cross-disciplinary studies involve collaborations with colleagues in the Faculty of Engineering (Professors Rob Krams and Ross Ethier, Department of Bioengineering; Professor Spencer Sherwin, Department of Aeronautics) to define flow dynamics at protected and susceptible regions of arteries.

Over the past five years, our group has discovered that high shear stress protects arteries from inflammatory activation by inducing negative regulators of the MAP kinase pathway and by altering the expression and function of NF-κB transcription factors. Thus we have identified several novel molecular mechanisms that may govern the spatial distribution of atherosclerotic plaques. Our recent work suggests that high shear stress may also influence endothelial activation by inducing Cezanne, a negative regulator of NF-κB that we cloned in 2001.

We intend to exploit our knowledge of atheroprotective mechanisms by developing strategies to induce protective genes or activate protective pathways at atherosusceptible sites. Indeed, we recently demonstrated that an isothiocyanate compound called sulforaphane can reduce inflammatory activation of EC at atherosusceptible sites by activating an anti-oxidant transcription factor called Nrf2. Our findings provide the first demonstration that pharmacological activation of a protective gene can reduce inflammation at atherosusceptible sites. Thus we propose that sulforaphane or its derivatives may have clinical utility for the prevention or treatment of vascular inflammation. As sulforaphane is derived from broccoli and related vegetables, our study also illuminates a novel potential mechanism for the beneficial effects of vegetable intake on cardiovascular health.

Systemic inflammatory responses to open-heart surgery

We are collaborating with Professor Dorian Haskard, Professor Gianni Angelini (Cardiothoracic Surgery) and Mr Thanos Athanasiou (Department of Surgery and Cancer) to study the molecular mechanisms that govern the systemic inflammatory response syndrome (SIRS) that can occur following coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB). Conventional CABG is carried out with the use of CPB, which provides a motionless and bloodless operating field to facilitate the surgical procedures. However, surgery with CPB can be associated with a spectrum of post-operative end-organ complications (including heart failure, renal impairment and neurological dysfunction) as a result of activation of systemic inflammatory responses. The contributors to the SIRS include operative surgical trauma, ischaemia and reperfusion of organs, gut-bacterial translocation and contact-activation of blood components after exposure to the artificial surfaces within the bypass circuit. Our studies of the molecular mechanisms that regulate SIR following CABG surgery may allow early diagnosis of inflammatory injury and inform the development of novel anti-inflammatory therapies.

• Prizes Awarded to group members

Selected publications

Chaudhury H, Zakkar M, Boyle J, Cuhlmann S, van der Heiden K, Luong LA, Davis J, Platt A, Mason JC, Krams R, Haskard DO, Clark AR, and Evans PC. (2010). c-Jun N-terminal kinase primes endothelial cells at atheroprone sites for apoptosis. Arterioscler. Thromb. Vasc. Biol. 30(3):546-53.

Zakkar M, Van der Heiden K, Luong LA,Chaudhury H, Cuhlmann S, Hamdulay SS, Krams R, Edirisinghe I, Rahman I, Carlsen H, Haskard DO, Mason JC, and Evans PC. (2009) Activation of Nrf2 in endothelial cells protects arteries from exhibiting a pro-inflammatory state. Arterioscler. Thromb. Vasc. Biol. 29(11):1851-7

Zakkar M, Chaudhury H, Sandvik G, Enesa K, Luong LA, Cuhlmann S, Mason JC, Krams R, Clark AR, Haskard DO and Evans PC. (2008) Increased endothelial MAP kinase phosphatase-1 expression suppresses pro-inflammatory activation at sites that are resistant to atherosclerosis. Circ. Res. 103, 726-732.

Enesa K, Zakkar M, Chaudhury H, Luong LA, Rawlinson L, Mason JC, Haskard DO, Dean JLE and Evans PC. (2008) NF-κB suppression by the deubiquitinating enzyme Cezanne: a novel negative feedback loop in pro-inflammatory signaling. J. Biol. Chem. 283 (11), 7036-7045.

Partridge J, Carlsen H, Enesa K, Chaudhury H, Zakkar M, Luong LA, Kinderlerer A, Johns M, Blomhoff R, Mason JC, Haskard DO and Evans PC. (2007) Shear stress acts as a switch to regulate divergent functions of NF-κB in endothelial cells: a potential novel mechanism for atheroprotection. FASEB J 21 (13), 3553-3561