Professor Catherine Shanahan BSc (Hons) PhD
Professor of Cellular Signalling
Department of Cardiology
The James Black Centre
125 Coldharbour Lane
London SE5 9NU
Professor Cathy Shanahan obtained her BSc(Hons) and PhD in Genetics from the University of Adelaide, Australia. She worked for CSIRO in Sydney, Australia before moving to the University of Cambridge as a post-doc in the Departments of Biochemistry and then Medicine. In 1995 she was appointed as a British Heart Foundation Basic Sciences Lecturer and in 2005 became a British Heart Foundation Senior Fellow in the Department of Medicine, University of Cambridge. In 2007 she took up the position of Professor of Cellular Signalling at King’s College London.
Professor Shanahan is currently a member of the British Atherosclerosis Society (BAS) and served on its committee from 2001-2004, is a nucleus member of the Atherosclerosis Working Group of the European Cardiac Society and is a member of the British Society of Cardiovascular Research (BSCR) and the North American Vascular Biology Organisation (NAVBO). She is currently on the Editorial Boards of Circulation Research (2011-), Arteriosclerosis, Thrombosis and Vascular Biology (2002-), Current Cardiology Reviews (2006-) and Kidney International (2007-).
The Molecular Regulation of Vascular Smooth Muscle Cell Phenotype
We are interested in the molecular regulation of vascular smooth muscle cell (VSMC) phenotype and how it relates to vascular dysfunction in diseases such as atherosclerosis, diabetes, hypertension, chronic renal failure and ageing.
Our studies have demonstrated that human VSMCs undergo a phenotypic transition when cultured in vitro. In culture, fully contractile human VSMCs convert into a ‘pan-mesenchymal cell’ with the capacity to express multiple lineage markers of smooth muscle, osteoblasts, chondrocytes and adipocytes. We hypothesize that similar phenotypic changes occur in vivo in the atherosclerotic plaque and during ageing and these modified, dysfunctional VSMCs contribute to vascular calcification and lipid accumulation and may apoptose or undergo cellular senescence.
VSMC-derived calcified matrix vesicles
A major area of interest is the regulation of vascular calcification, a detrimental process that occurs in the vessel media and in the atherosclerotic plaque. Our studies on vascular calcification in the context of atherosclerosis, diabetes and chronic renal failure have shown that it is a regulated process similar to bone formation. VSMCs in the normal artery wall constitutively express potent inhibitors of calcification, such as matrix Gla protein (MGP), whose absence results in spontaneous medial calcification. In atherosclerotic calcification and diabetic Monckeberg’s Sclerosis, expression of inhibitors is reduced and VSMCs express markers of both osteoblast (alkaline phosphatase, bone sialoprotein and osteocalcin) and chondrocyte (collagen II) differentiation. Human VSMCs in culture spontaneously convert to an osteo/chondrocytic phenotype, express the obligate bone transcription factor Cbfa1/Runx2 and form calcified nodules. Calcification is initiated in nodules by release of apoptotic bodies (AB) and matrix vesicle (MV)-like structures from VSMCs that act as a nidus for hydroxyapatite nucleation. In addition, circulating proteins present in serum such as fetuin-A have also been identified as potent inhibitors of calcification. Our studies are aimed at determining the pathological processes that accelerate VSMC phenotypic change and subsequent calcification. We are particularly interested in the role of matrix vesicles in acting as the initial nidus for VSMC calcification and we have demonstrated that extracellular calcium and phosphate are key regulators of matrix vesicle mediated calcification.
More recently we have begun to focus our work on determining the role of cellular ageing in driving the calcification process. We have identified nuclear lamina dysfunction as a specific pathway driving VSMC ageing and calcification. This process is driven by the accumulation of unprocessed prelamin A and mimics the ageing process observed in children with premature ageing disorders such as Progeria which are caused by specific mutations in the nuclear envelope protein lamin A.
Prelamin A accumulation and nuclear morphology defects in an aged VSMC
The Nesprin Family of Proteins in Cardiovascular Cell Function
Using differential cDNA screening to discover VSMC differentiation markers we identified a novel family of proteins called Nesprins. Nesprins are a family of multi-isomeric scaffolding proteins that were originally identified at the nuclear envelope (NE), where they bind to lamin A/C, emerin and SUN-domain containing proteins, to form the LInker of Nucleoskeleton-and-Cytoskeleton (LINC) complex that connects the NE to the cytoskeleton.
In VSMCs we are studying the role of nesprins in RNA processing, cell migration, cell ageing and nuclear and cytoplasmic stress signalling pathways.
Nesprins are also highly expressed in cardiac and skeletal muscle and localise to the Z-disk and A/I junction of the sarcomere, in addition to the NE. We have shown that mutations in either nesprin-1 or 2 are causative in Emery Dreifuss muscular dystrophy and dilated cardiomyopathy, highlighting their importance in muscle.
We are now focusing on defining the roles of nesprins in cardiac cell function by employing molecular/cell biology and biochemical techniques to determine the functional significance of novel nesprin-1 mutations on the LINC complex and to identify novel roles for nesprins in the sarcomere. This will further our understanding of the functions of nesprins in cardiac muscle, and may reveal novel pathways that contribute to the development of cardiac cell dysfunction and cardiomyopathy.
Senior Research Associate
BHF Intermediate Fellow
Dr A Kapustin
- Dr Y Liu
- Dr A Cobb
- Dr F Autore (joint with Randall Division)
Jayanta Bordoloi (joint with Division of Imaging Sciences)
Dr Sundeep Kalra (Clinical)
Dr Nina Petrova (Clinical)