Research focuses on the autocrine / paracrine control of cardiovascular dysfunction and the role of oxidative stress.
Many investigations in this laboratory have examined important peptide mediators and their receptor systems: e.g. neuropeptide Y (NPY) and its contractile and pro-hypertrophic effects through Y1, Y2 and Y5 receptors. Enhancement of NPY potency producing opposing Y1 and Y2 contractile effects, together with unchanged maximal response, enables NPY to contribute to regulating cardiac performance during compensatory left ventricular hypertrophy.
Current research centres on the cytoprotective actions of the calcitonin gene-related peptide (CGRP) family, including adrenomedullin (AM) and more recently discovered AM-2, now called intermedin (IMD):
- released from fibroblasts, endothelial and vascular smooth muscle cells, and cardiomyocytes;
- enhanced by hypoxia / oxidative stress in vitro, hypertension (angiotensin II, catecholamines);
- reduces left ventricular hypertrophy, fibrosis, oxidative stress;
- is pro-angiogenic.
Using the CGRP-adrenomedullin (AM) receptor model, objectives are to:
- investigate if IMD and/or RAMP1 overexpression by adenoviral transfer in vivo can prevent phenotypic changes induced by oxidative stress;- establish that IMD/RAMP1 can directly reduce effects of known oxidants in cardiomyocytes, and compare with CGRP’s functional effects and signalling;
- ascertain that prevention of upregulation of IMD/RAMP1 using RNA interference approaches will exacerbate consequences of oxidative stress;
- investigate anti-hypertrophic effects of IMD and pro-angiogenic signalling through RAMP2.
Collaborators: Andrew Russo, University of Iowa
Lee and Julie Chao, Medical University of South Carolina
Dayuan Sui, Jilin University
Other CVVS projects as collaborator
Protective role of glucagon like peptide-1 in cardiac remodeling after myocardial infarction - with David Grieve (PI) and Emma Robinson (PDRA).
MicroRNA regulation of cardiac Kir channel expression – with Tony Collins (PI) and Mary McGahon (PDRA).
Molecular mechanisms associated with doxorubicin-induced cardiotoxicity through NADPH oxidase – with David Grieve and Declan McLaughlin (PhD student).
Interaction between peroxisome proliferator-activated receptor-a and NADPH oxidases during the progression of hypertensive cardiac remodeling – with David Grieve and Adam Harvey (PhD student).