Angel qualified as a molecular biologist (BSc, MSc) in 1990 from the Universidad Complutense de Madrid, Spain, before moving to the Life Science Division, King’s College London to undertake post-graduate research studies.
In 1995 Angel obtained his PhD from the Molecular Biology Department, Universidad Autonoma de Madrid, Spain, and began post-doctoral studies into the molecular mechanisms involved in the regulation of signal transduction pathways. In 1998 he began a second postdoctoral study at the Cancer Research UK laboratories, London, and Paterson Institute for Cancer Research, Manchester, where he focused on the implications of transcription factors in cancer progression.
Angel took a lectureship in 2001 at the University of Manchester where he investigated the molecular basis of cardiac hypertrophy and heart failure.
In 2005 Angel joined the University of Wolverhampton as Reader in Molecular Pharmacology. He lectures on molecular pharmacology and leads a research team investigating the molecular mechanisms implicated in cardiovascular disease.
Cardiovascular Molecular Medicine, with particular reference to signal transduction regulation in pathological angiogenesis.
Current Research Projects
- Characterisation of the molecular mechanisms that regulate angiogenesis in the heart after myocardial infarction
Ischemic heart disease is the leading cause of morbidity and mortality in the Western world. Cardiac ischemia activates vascular regrowth responses in the heart to protect the myocardial tissue against the ischemic condition by sprouting existing capillaries (angiogenesis) and by developing collateral vessels (arteriogenesis) that bypass the area of stenosis or occlusion. Unfortunately, patients with similar degrees of coronary stenosis show a marked variability in the development of new capillary and collateral arterial vessels, and reperfusion of the ischemic heart is not efficient in many cases. Moreover, formation of new blood vessels is significantly impaired in patients with type 2 diabetes, metabolic syndrome, and severe atherosclerosis. We are studying the molecular mechanisms that regulate reparative angiogenesis and collateral development in the ischemic heart to use this information for the design of efficient therapeutic interventions that promote myocardial revascularization in patients with occluded arteries.
- Role of the Plasma Membrane Calcium ATPase proteins as regulators of abnormal blood vessel formation in cardiovascular disease
The Plasma Membrane Calcium ATPase proteins (PMCAs) are enzymatic low-capacity high-affinity systems involved in the extrusion of Ca2+ from the cell. In humans there are four different PMCA isoforms, PMCA1–4, that are encoded by four independent genes. Studies in recent years have uncovered an increasingly important role for PMCAs as regulators of signal transduction pathways via interaction with specific partner proteins. We have recently reported a novel role for PMCA4 as a negative regulator of VEGF-dependent angiogenesis via interaction with the signalling phosphatase calcineurin. It is well established that VEGF-dependent activation of the calcineurin/NFAT pathway plays a critical role in the progression of pathological angiogenesis. We believe that targeted modulation of PMCA4 functionality might be used to design new therapeutic interventions to promote or attenuate angiogenesis in patients experiencing angiogenic disorders.
- Mr Sathishkumar Kurusamy (PhD student)
- Mr Jude Ihugba (PhD student)
- Dr David Cadagan (Post-doctoral research scientist)
- Professor Weiguang Wang (University of Wolverhampton, UK)
- Dr Farjana Rowther (University of Wolverhampton, UK)
- Professor James Cotton (Consultant Cardiologist, Wolverhampton NHS New Cross Hospital)
- Professor Juan Miguel Redondo (Centro Nacional de Investigaciones Cardiovasculares, CNIC, Madrid, Spain)
- Dr Ana Mata and Dr Isaac Corbacho (Universidad de Extremadura, Badajoz, Spain)
- Dr Elizabeth Cartwright (University of Manchester, UK)
- Dr Allan Lawrie (University of Sheffield, UK)
- Dr Rob Wilkinson (University of Sheffield, UK)
- Dr Michael Emerson (Imperial College London, UK)
- Member of the British Microcirculation Society
- Member of the European Society for Microcirculation
- Member of the British Society for Cardiovascular Research
- Little R, Zi M, Hammad SK, Nguyen L, Njegic A, Kurusamy S, Prehar S, Armesilla AL, Neyses L, Austin C, Cartwright EJ. Reduced expression of PMCA1 is associated with increased blood pressure with age which is preceded by remodelling of resistance arteries. Aging Cell (2017) 16(5):1104-1113.
- Kurusamy S, López-Maderuelo D, Little R, Cadagan D, Savage AM, Ihugba JC, Baggott RR, Rowther FB, Martínez-Martínez S, Arco PG, Murcott C, Wang W, Francisco Nistal J, Oceandy D, Neyses L, Wilkinson RN, Cartwright EJ, Redondo JM, Armesilla AL. Selective inhibition of plasma membrane calcium ATPase 4 improves angiogenesis and vascular reperfusion. J Mol Cell Cardiol (2017) 109:38-47.
- Wang Z, Tan J, McConville C, Kannappan V, Tawari PE, Brown J, Ding J, Armesilla AL, Irache JM, Mei QB, Tan Y, Liu Y, Jiang W, Bian XW, Wang W. Poly lactic-co-glycolic acid controlled delivery of disulfiram to target liver cancer stem-like cells. Nanomedicine (2017) 13(2):641-657.
- Amoah V, Wrigley B, Holroyd E, Smallwood A, Armesilla AL, Nevill A, Cotton J. Vascular endothelial growth factor and hypoxia-inducible factor-1α gene polymorphisms and coronary collateral formation in patients with coronary chronic total occlusions. SAGE Open Med (2016) 4:2050312116654403.
- Oller J, Alfranca A, Méndez-Barbero N, Villahoz S, Lozano-Vidal N, Martín-Alonso M, Arroyo AG, Escolano A, Armesilla AL, Campanero MR, Redondo JM. C/EBPβ and Nuclear Factor of Activated T Cells Differentially Regulate Adamts-1 Induction by Stimuli Associated with Vascular Remodelling. Mol Cell Biol (2015) 35(19):3409-22.
- Liu P, Wang Z, Brown S, Kannappan V, Tawari PE, Jiang W, Irache JM, Tang JZ, Armesilla AL, Darling JL, Tang X, Wang W. Liposome encapsulated Disulfiram inhibits NFκB pathway and targets breast cancer stem cells in vitro and in vivo. Oncotarget (2014) 5(17):7471-85.
- Baggott RR, Alfranca A, López-Maderuelo D, Mohamed TM, Escolano A, Oller J, Ornes BC, Kurusamy S, Rowther FB, Brown JE, Oceandy D, Cartwright EJ, Wang W, Gómez-del Arco P, Martínez-Martínez S, Neyses L, Redondo JM, Armesilla AL. Plasma membrane calcium ATPase isoform 4 inhibits vascular endothelial growth factor-mediated angiogenesis through interaction with calcineurin. Arterioscler Thromb Vasc Biol (2014) 34(10):2310-20.
- Liu P, Kumar IS, Brown S, Kannappan V, Tawari PE, Tang JZ, Jiang W, Armesilla AL, Darling JL, Wang W. Disulfiram targets cancer stem-like cells and reverses resistance and cross-resistance in acquired paclitaxel-resistant triple-negative breast cancer cells. Br J Cancer (2013) 109(7):1876-85.
- Amoah V, Storey RF, Worrall AP, Goodridge K, Lovatt T, Smallwood A, Armesilla AL, Nevill AM, Cotton JM. Near patient anti-platelet response testing over time and gene analysis in patients admitted with acute coronary syndromes. Platelets (2013) 24(8):643-8.
- Liu P, Brown S, Goktug T, Channathodiyil P, Kannappan V, Hugnot JP, Guichet PO, Bian X, Armesilla AL, Darling JL, Wang W. Cytotoxic effect of disulfiram/copper on human glioblastoma cell lines and ALDH-positive cancer-stem-like cells. Br J Cancer (2012) 107(9):1488-97.
- Baggott RR, Mohamed TM, Oceandy D, Holton M, Blanc MC, Roux-Soro SC, Brown S, Brown JE, Cartwright EJ, Wang W, Neyses L, Armesilla AL. Disruption of the interaction between PMCA2 and calcineurin triggers apoptosis and enhances paclitaxel-induced cytotoxicity in breast cancer cells. Carcinogenesis (2012) 33(12):2362-8.
- Amoah V, Smallwood A, Worrall AP, Lovatt T, Armesilla AL, Nevill AM, Cotton JM. Poor aspirin response in diabetic patients presenting with acute coronary syndromes: results using a near patient test. Thromb Res (2011) 128(2):196-9.
- Yip NC, Fombon IS, Liu P, Brown S, Kannappan V, Armesilla AL, Xu B, Cassidy J, Darling JL, Wang W. Disulfiram modulated ROS-MAPK and NFκB pathways and targeted breast cancer cells with cancer stem cell-like properties. Br J Cancer (2011) 104(10):1564-74.
- Holton ML, Wang W, Emerson M, Neyses L, Armesilla AL. Plasma membrane calcium ATPase proteins as novel regulators of signal transduction pathways. World J Biol Chem (2010) 1(6):201-8.
- Amoah V, Worrall AP, Smallwood A, Armesilla AL, Nevill AM, Cotton JM. Clopidogrel and proton pump inhibitors: can near patient testing help in the tailoring of dual antiplatelet prescription? J Thromb Haemost (2010) 8(6):1422-4.
- Holton M, Mohamed TM, Oceandy D, Wang W, Lamas S, Emerson M, Neyses L, Armesilla AL. Endothelial nitric oxide synthase activity is inhibited by the plasma membrane calcium ATPase in human endothelial cells. Cardiovasc Res (2010) 87(3):440-8.
- Xu B, Guo X, Mathew S, Armesilla AL, Cassidy J, Darling JL, Wang W. Triptolide simultaneously induces reactive oxygen species, inhibits NF-kappaB activity and sensitizes 5-fluorouracil in colorectal cancer cell lines. Cancer Lett (2010) 291(2):200-8.
- Guo X, Xu B, Pandey S, Goessl E, Brown J, Armesilla AL, Darling JL, Wang W. Disulfiram/copper complex inhibiting NFkappaB activity and potentiating cytotoxic effect of gemcitabine on colon and breast cancer cell lines. Cancer Lett (2010) 290(1):104-13.
- Oceandy D, Pickard A, Prehar S, Zi M, Mohamed TM, Stanley PJ, Baudoin-Stanley F, Nadif R, Tommasi S, Pfeifer GP, Armesilla AL, Cartwright EJ, Neyses L. Tumor suppressor Ras-association domain family 1 isoform A is a novel regulator of cardiac hypertrophy. Circulation (2009) 120(7):607-16.
- Holton M, Yang D, Wang W, Mohamed TM, Neyses L, Armesilla AL. The interaction between endogenous calcineurin and the plasma membrane calcium-dependent ATPase is isoform specific in breast cancer cells. FEBS Lett (2007) 581(21):4115-9.
- Guo X, Evans TR, Somanath S, Armesilla AL, Darling JL, Schatzlein A, Cassidy J, Wang W. In vitro evaluation of cancer-specific NF-kappaB-CEA enhancer-promoter system for 5-fluorouracil prodrug gene therapy in colon cancer cell lines. Br J Cancer (2007) 97(6):745-54.
- Oceandy D, Cartwright EJ, Emerson M, Prehar S, Baudoin FM, Zi M, Alatwi N, Venetucci L, Schuh K, Williams JC, Armesilla AL, Neyses L. Neuronal nitric oxide synthase signaling in the heart is regulated by the sarcolemmal calcium pump 4b. Circulation (2007) 115(4):483-92.
- Williams JC, Armesilla AL, Mohamed TM, Hagarty CL, McIntyre FH, Schomburg S, Zaki AO, Oceandy D, Cartwright EJ, Buch MH, Emerson M, Neyses L. The sarcolemmal calcium pump, alpha-1 syntrophin, and neuronal nitric-oxide synthase are parts of a macromolecular protein complex. J Biol Chem (2006) 281(33):23341-8.
- Buch MH1, Pickard A, Rodriguez A, Gillies S, Maass AH, Emerson M, Cartwright EJ, Williams JC, Oceandy D, Redondo JM, Neyses L, Armesilla AL. The sarcolemmal calcium pump inhibits the calcineurin/nuclear factor of activated T-cell pathway via interaction with the calcineurin A catalytic subunit. J Biol Chem (2005) 280(33):29479-87.
Examples of Recently Completed PhD Programmes as principal supervisor
- Role of the Plasma Membrane Calcium ATPase as a Negative Regulator of Angiogenesis.
Student: Rhiannon Baggott. Completion: August 2014
- PMCA as a regulator of calcium/calmodulin-dependent signal transduction pathways.
Student: Mary Holton. Completion: October 2009
- Functional interaction between the sarcolemmal PMCA and the phosphatase calcineurin.
Student: Mamta Buch. Completion: June 2007
- A functional investigation of the PMCA4b-RASSF1A interaction, and of RASSF1A in a cellular model of hypertrophy.
Student: Adam Pickard. Completion: April 2007
Examples of Potential PhD Programmes
- Characterization of the molecular nature of the PMCA4/Calcineurin interaction in human cardiac endothelial cells.
- Gene expression signature in endothelial cells during cardiovascular disease.
- Role of the Plasma Membrane Calcium ATPase proteins in the progression of pulmonary arterial hypertension.
- Circulating levels of microRNAs in plasma samples of myocardial infarction patients (in collaboration with Prof James Cotton, Wolverhampton NHS New Cross Hospital).
- Role of the transcription factor ATF2 in pathological angiogenesis.