Investigating The Role Of TRPA1 In Cardiovascular Regulation

Jennifer V. Bodkin, Aisah A. Aubdool, Susan D. Brain. BHF Centre of Excellence and Centre for Integrative Biomedicine, Kings College London,, London, UK

Transient Receptor Potential Ankyrin 1 (TRPA1) channels are non selective cation channels, predominantly expressed on small diameter sensory neurones. TRPA1 is activated by noxious compounds, including exogenous agonists such as mustard oil and cinnamaldehyde. In vivo, TRPA1 channels are suggested to be activated by ROS and products of oxidative stress (Andersson et al, 2008). A growing number of publications have demonstrated TRPA1 agonists to mediate vasodilatation responses (See review by Bodkin and Brain, 2010). We were the first to demonstrate a potential cardiovascular role for the receptor, using TRPA1 KO mice and exogenous agonists (Pozsgai et al, 2010).

As peripheral blood vessel tone is an important component of peripheral resistance and blood pressure control, we have conducted a novel cardiovascular characterisation study. TRPA1 WT and KO mice were profiled by telemetry (PA-C10 probe catheterising the left carotid artery) and echocardiography (VEVO 770) at baseline. They then underwent experimental hypertension using subcutaneously implanted osmotic minipumps infusing angiotensin II (1.1mg/kg/day) for 14 days, in a similar manner to that described in Liang et al, 2009). This additional pathological stress was designed to exacerbate the effect of TRPA1 deletion. Mice were characterised throughout the infusion period and then terminated under isoflurane anaesthesia. Organs from these mice were then collected and analysed for levels of remodelling and inflammatory biomarkers using ex vivo methods, including ELISA and quantitative PCR and histological Massons Trichrome staining.

Mixed gender TRPA1 WT and KO mice (25-30g) displayed similar basal blood pressure (daytime systolic bp WT 113+/-16mmHg n = 7 KO 117+/-8mmHg n = 10). During angiotensin II infusion, both genotypes experienced significant hypertension (daytime systolic bp WT 162+/-18mmHg n = 6 KO 161+/-23mmHg n = 6) with similar onset profiles.

TRPA1 WT and KO mice both showed significant cardiac and vascular hypertrophy following angiotensin II infusion. Additionally, TRPA1 receptor gene expression was significantly increased in TRPA1 WT DRG. However, angiotensin II treated TRPA1 KO mice displayed a lower IL-6 (Heart expression WT Ang II 55475+/-32532 copies/μl n = 14 KO Ang II 32107+/-20134 copies/μl n = 17 *p<0.05) and MCP-1 (Aorta expression WT Ang II 23137+/-5437copies/μl n = 6 KO Ang II 11929+/-5741 copies/μl n = 9 *p<0.05) gene expression during hypertension, compared to angiotensin II treated WT mice. Statistics are one-way ANOVA with Tukey’s post test.

Our novel study is the first to investigate the role of TRPA1 in cardiovascular regulation. Our data show TRPA1 KO mice display no basal cardiovascular phenotype and respond similarly in angiotensin II induced hypertension to WT mice. However, differences were found in terms of blunted IL-6 and MCP-1 expression/release in KO mice. These findings need further investigation but suggest TRPA1 has limited influences on the control of systemic blood pressure.

Andersson et al,2008, Neurosci, 28(10), 2485-94

Bodkin and Brain, 2010, Acta Physiol, 15, 1748-1716.

Liang et al, 2009, Hypertension, 54(6),1254-61

Pozsgai et al, 2010, Cardiovasc. Res., 87(4), 760-8.

JVB is a BHF PhD Student

AAA is a BBSRC PhD Student