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Dr. Hope Anderson
– Vascular Biology
Dr. Hope Anderson
Principal Investigator, Vascular Biology & Assistant Professor, Faculty of Pharmacy
University of Manitoba
Research Focus
- Cardioprotective effects of CLA, a dietary polyunsaturated fatty acid that occurs naturally in dairy and meat products from ruminant animals.
- Elucidation of novel signaling mechanisms underlying cardiac hypertrophy. A specific example includes epidermal growth factor receptor signaling in the nucleus of heart muscle cells.
- Mechanisms of defective artery function in hypertension, and effects of candidate dietary interventions.
Why is this work important?
In medical practice, emphasis is now routinely placed on dietary modification as a preventative measure to forestall cardiovascular disease. Unfortunately, fully exploiting the preventative value of nutritional intervention is posing a huge challenge given the complex interaction between diet and bodily function. We need more information about specific dietary approaches and how they work. The goal of our research program is to understand how risk factors for cardiovascular disease, especially diabetes, hypertension, and cardiac hypertrophy, promote the development of heart failure. Our ultimate aim is to identify new therapies, from a nutritional perspective, that prevent or slow the onset of heart failure.
What techniques and equipment are used in this laboratory?
- in vivo study of cardiovascular disease: echocardiography, tail-cuff plethysmography
- in vitro study of cardiac hypertrophy: cell culture, confocal microscopy, planimetry, promoter-reporter assays, biochemical assays (immunoblotting, immunoprecipitation, etc)
- in vitro study of arteries: pressure myography
About Hope Anderson
Dr. Anderson obtained her PhD in Pharmacology and Therapeutics (University of Manitoba), followed by post-doctoral fellowships at the Clinical Research Institute of Montreal and the University of California at San Francisco. As a recipient of the prestigious Canadian Institutes of Health Research (CIHR) New Investigator Award, Dr. Anderson has published extensively in her research areas of cardiovascular disease, insulin resistance, and natural health products. She has served on advisory boards of the CIHR and Heart and Stroke Foundation (HSF) of Canada. Dr. Anderson’s research has been funded by the CIHR, HSF of Manitoba, Canada Foundation for Innovation, Manitoba Medical Services Foundation and University of Manitoba Research Grants Program.
For more information, please contact:
Dr. Hope Anderson
Tel. 204.235.3587
Fax. 204.231.1151
Email. handerson@sbrc.ca
In Detail
Effect of conjugated linoleic acid on cardiac hypertrophy
As heart failure patients are increasingly turning to nutrition-based therapies, it is imperative that we identify safe and effective dietary interventions that slow or prevent the transition from cardiac injury to heart failure. We are excited about our novel finding that conjugated linoleic acid (CLA), a dietary polyunsaturated fatty acid and nutraceutical, prevents cardiac hypertrophy. We know that CLA traffics through peroxisome proliferator-activated receptors to suppress hypertrophic growth and signaling. These data are submitted to the Journal of Biological Chemistry. We are now probing the upstream mechanisms that are invoked by CLA. Potential targets under scrutiny include calcineurin and diacylglycerol kinase. We are also assessing therapeutic potential of CLA by determining isomer-specificity, absence or existence of side effects such as fluid retention, and effects on established heart disease.
Effect of dietary chromium on resistance artery function and nitric oxide signaling in the sucrose-fed spontaneously hypertensive rat.
Consumption of high-glycemic index foods can contribute to the development of hypertension. We investigated whether trivalent chromium, which is generally considered an essential trace metal, lowers blood pressure by improving arterial relaxation. Our findings indicate that the ability of Cr3+ to selectively prevent sucrose-induced but not basal hypertension in spontaneously hypertensive rats involves improving vasodilatory function by restoration of nitric oxide signaling in resistance arteries. These findings were published in the Journal of Vascular Research. Currently, we are using isolated vascular endothelial and smooth muscle cells to elucidate the mechanisms underlying the ability of Cr3+ to modulate eNOS and PKG-1β gene expression.
Regulation of cerebral blood flow by vascular N-methyl-D-aspartate (NMDA) receptors.
This research is investigating a novel astrocyte-mediated signaling mechanism for functional hyperemia, in which astrocytes influence cerebral blood flow by releasing vasoactive D-serine during enhanced neuronal activity. D-serine is an agonist for the NMDA receptor regulatory glycine site. In the brain, it is compartmentalized to astrocytes and released as a gliotransmitter. This is a collaboration with Dr. Chris Anderson (Division of Neurodegenerative Disease, St. Boniface Hospital Research Centre) who is lead investigator. My contribution is characterization of the vasoactive actions of D-serine in isolated cerebral microvessels (lumen diameter ~60 µm) using our pressure myograph system. We are also assisting Dr. C. Anderson with detection of NMDA receptor subunits in the cerebral microvasculature.Influence of ductal decompression of the pulmonary circuit on vascular myogenic response in hypoxic pulmonary hypertension of the newborn. This project examines the influences of hypoxia and pulmonary flow on the onset of pulmonary arterial hypertension in neonates. The primary hypothesis is that wall strain exacerbates myogenic response and remodeling of pulmonary vasculature in early hypoxic pulmonary hypertension, and that decompression of the pulmonary circuit via patent ductus arteriosus may act as a protective mechanism against the onset of smooth muscle proliferation and/or mural fibrosis. Thus, patency of the ductus arteriosus is manipulated in newborn piglets on the first day of life by interventional catheterization (i.e. DA stented open or coiled closed). The piglets are then raised in hypoxic or normoxic conditions for next 72 hours. Immediate endpoints of interest are [1] altered pulmonary hemodynamics; [2] histology, including morphometry to assess remodeling; [3] wall stiffness, measured by passive stress/strain/elastance indices. This is a collaborative effort with Dr. Shyamala Dakshinamurti (Pediatrics and Child Health, University of Manitoba) as lead investigator. My contribution to the project is determination of vessel wall mechanics (stiffness, distensibility) using our pressure myography apparatus.
The role of calreticulin in the regulation of vascular wall during embryonic development and disease development.
Calreticulin is an endoplasmic reticulum resident chaperone that plays important roles in Ca2+ homeostasis and cell adhesion. In addition, calreticulin has been demonstrated to play a critical role in cardiovascular development in mice. In collaboration with lead investigator Dr. Nasrin Mesaeli (Institute of Cardiovascular Sciences, St. Boniface Research Centre), we studied the role of calreticulin on regulation of vascular structure and function using two transgenic mouse models that overexpress calreticulin in the vascular smooth muscle or endothelial cells. Our contribution to this project was determination of vascular geometry, mechanics, and relaxatory function of isolated arteries from these mice using our pressure myography apparatus.
Role of epidermal growth factor receptor (EGFR) activation in stretch-induced hypertrophy of cardiac myocytes.
It is important to understand the mechanisms underlying the development of cardiac hypertrophy which progresses to heart failure. I elucidated a mechanism by which the brain natriuretic peptide (BNP) gene, as a member of the fetal gene program, is reactivated during hypertrophy. Mechanical strain of cardiac myocytes stimulates NAD(P)H oxidase activity which in turn generates free radicals. These promote the production of endothelin-1 which induces metalloproteinase-dependent cleavage of membrane-bound HBEGF, a ligand for the EGF receptor (EGFR). Liganded EGFR autophosphorylates, recruits Src tyrosine kinase, and then signals through protein kinase C and ERK to increase BNP promoter activity. These findings have significant import, particularly since metalloproteinases and HBEGF are membranous and accessible therapeutic targets. These studies were published in The Journal of Biological Chemistry in 2004.
Elucidation of the mechanisms underlying repressive effects of TNF-α on Endothelial Nitric Oxide Synthase.
This project tested the hypothesis that a mediator of insulin resistance, tumor necrosis factor-a (TNF-α), reduces expression of eNOS, the enzyme that catalyzes production of nitric oxide (NO). NO produced by endothelial cells plays a key role in maintaining vascular tone and structure. Using cultured bovine aortic endothelial cells, I determined that physiological concentrations of TNF-α reduce eNOS levels and activity by repressing eNOS promoter activity. I implicated the NF-κB in these effects of TNF-α using dominant negative mutant experiments. Scanning the human eNOS promoter, I implicated an Sp1/Sp3 element in mediating the repressive effect of TNF-α on eNOS. Understanding the inhibitory mechanisms invoked by TNF-α is significant because clinically, it is known that TNF-α depresses vascular endothelial function, for example, in patients with heart failure. These findings were published in The Journal of Biological Chemistry in 2004.
