Dr. Peter Zahradka
Deputy Team Leader, CCARM
Molecular Physiology, Canadian Centre for Agri-food Research in Health and Medicine
Departments of Physiology and Pathophysiology & Human Nutritional Sciences, University of Manitoba
The Molecular Physiology laboratory has a long-standing interest in the cellular and molecular processes that control the functional properties of blood vessels. Our research in this area is going in two distinct directions. First, we are attempting to understand the properties of blood vessels as they relate to the repair of damaged sections, and we are particularly interested in understanding why the cells of blood vessels continue to divide even after the repair is complete. If these cells continue to grow and divide, the result is the formation of a lesion that can interfere with blood flow. While most people understand that atherosclerosis is a condition of aging, the formation of lesions as a result of interventions such as angioplasty and bypass surgery, also known as restenosis, is not as well known. Like atherosclerosis, restenosis can also have life threatening consequences, however, these occur within 6-12 months after a procedure, whereas atherosclerosis is a slow process that requires decades to become an issue. Our research is focused on the identification of new targets for therapeutic prevention of restenosis.
Second, the laboratory is investigating whether nutritional intervention with novel supplements or food products can be used in the treatment or prevention of cardiovascular disease. In this case, atherosclerosis is the main focus of this work. We have obtained novel equipment to assess hardening of the arteries in both humans and animals, thus providing us with the capability to directly compare results obtained in clinical trials with those of animal studies. This will give us a huge advantage when we are ready to translate the laboratory findings to the public. Specifically, we are interested in identifying and characterizing new bioactive molecules from plants, and employing both animal and human studies to examine efficacy and safety of these molecules. Our proficiency in cell culture and analytical chemistry will also help us in determining which biological factors that mediate blood vessel function are influenced by specific bioactive ingredients in our food, especially in the context of atherosclerosis, obesity and diabetes. Given the importance of diet to these diseases, nutritional intervention is an important component of this work.
Why is this work important?
Our work with smooth muscle cell proliferation has relevance to clinical interventions such as balloon angioplasty and bypass grafting, since these procedures result in considerable damage to the vessel wall and the formation of restenotic lesions. The identification of two classes of inhibitors that exhibit efficacy in a pig model of restenosis is particularly valuable, especially since these compounds have not been found to have deleterious effects on the tissues. The ability to transiently apply inhibitors to the surface of blood vessels is also seen as an advance in treatment for bypass graft procedures. Our work with various nutritional interventions has shown that bioactive compounds derived from plant and animal sources may be applicable to the treatment of obesity-associated diseases, including atherosclerosis and metabolic syndrome. In particular, we have been able to establish that short-term changes in what we eat can affect the health of our blood vessels. These results provide us with strong rationale to move forward with testing other food products that have the potential to improve human health.
What techniques and equipment are used in this laboratory?
Some of our studies are conducted with cell culture models. We have cells that were derived from blood vessels (smooth muscle, endothelial), liver, adipose, colon, skeletal muscle and kidney tissues. These are available for monitoring the effects of growth factors, hormones and differentiation factors, or to help identify novel bioactive compounds and their mechanism of action. We also have access to animal models of obesity, diabetes and cardiovascular disease, and we have the capability to conduct studies with human volunteers. We have been studying signal transduction processes utilizing Western blotting and proteomic approaches. In addition, we can introduce recombinant DNA or small interfering RNAs into cells and animals with viruses. Finally, our access to human subjects has not only enabled us to decipher the way the food we eat affects our health, it has also allowed us to apply genomics to our examination of how nutritional factors influence vascular and metabolic disease.
About Dr. Peter Zahradka
Dr. Zahradka completed his undergraduate and graduate degrees at the University of Western Ontario in the Department of Biochemistry. He subsequently conducted post-doctoral studies at Stanford University (Laboratory of Experimental Oncology) and the University of Guelph (Molecular Biology and Genetics) before being hired as an assistant professor/sessional lecturer in the Department of Chemistry and Biochemistry at Guelph. After two years teaching 4 courses per year, he moved to the University of Manitoba where he joined the Department of Physiology as a member of the Division of Cardiovascular Sciences at the St. Boniface Research Centre. He has since been promoted from contingent assistant professor to tenured full professor and has seen the original division become the Institute of Cardiovascular Sciences. Finally, after 15 years with the Institute of Cardiovascular Sciences, he took over as Team Leader of the Canadian Centre for Agri-food Research in Health and Medicine (CCARM) in 2006. He has helped the unit grow from its original 3 scientists to 12 scientists who now occupy the entire second floor. In 2012, he also became head of the Division of Endocrinology and Metabolic Disease in the Department of Physiology, a role that fits well with his research program.
For more information, contact:
Dr. Peter Zahradka
Tel. (204) 235-3507
Fax. (204) 237-2289
Vascular Disease and Obesity: It is a well-established fact that obesity is closely linked with atherosclerosis, the underlying cause of coronary artery disease and peripheral vascular disease. Atherosclerosis is a disease of the blood vessels that begins when the lining of the vessels (or endothelium) is disrupted. In its most severe state, lesions capable of severely restricting blood flow are present. If these lesions block the vessels of key organs such as the heart, death may result. The reason obesity is associated with vascular disease is because atherosclerosis develops faster when blood lipid (cholesterol, triglycerides) levels are elevated. Interestingly, there is now strong evidence to suggest that hormones produced by adipose (fat storing) tissue help with maintaining the health of blood vessels. It has therefore been proposed that an alteration in the production of these hormones as a result of obesity may trigger or promote atherosclerosis.
The Diabetes Connection: Individuals with diabetes (either type 1 or type 2) have a higher risk of developing atherosclerosis than the normal population, independent of their body mass. Furthermore, atherosclerosis progresses faster with diabetes. Consequently, cardiovascular disease is the primary cause of death for people with diabetes. It has been recently recognized that diabetes alters hormone production by adipose tissue, and that this change in hormone levels likely is responsible for stimulating atherosclerosis.
Targeting Adipokine Production to Treat Vascular Disease: Pharmaceutical agents provide their health benefits by impeding or augmenting specific cellular processes. Natural compounds present in a food product or delivered in pill form can achieve similar results. Consequently, there is considerable interest in developing functional foods and nutraceuticals as alternatives to pharmaceuticals. Our research has been aimed at identifying foods that contain compounds capable of preventing the onset or slowing the progression of vascular disease. We have found that conjugated linoleic acid (CLA) will elevate serum levels of adiponectin, a potent anti-atherosclerotic hormone produced by adipose tissue. We have shown that adiponectin affects blood vessels by preventing the first step of atherosclerosis: smooth muscle cell proliferation and migration. In addition, this adipokine is likely responsible for the reduction in renal failure, pancreatic dysfunction and liver steatosis that occurs in obese rats. Our studies have also been able to show that infusing adiponectin can decrease blood pressure in obese rats. A major finding has been the identification of thrombin as a key factor in the blood that regulates adiponectin activity. Since thrombin is important for blood clotting, we are proposing that adiponectin has a role in how blood vessels respond to injury.
Cell and Molecular Biology of Vascular Disease: Our research is also directed towards understanding the vascular response to injury, which is a key factor in the development of atherosclerotic disease. By identifying the cellular mechanisms responsible for triggering smooth muscle cell proliferation and migration, we expect to develop approaches for preventing disease progression. Our investigation of angiotensin II-stimulated smooth muscle cell proliferation, which is intended to identify the regulatory mechanisms responsible for mediating the biological actions of this hormone, has been a major focus of the lab. We have made substantial progress on several fronts. First, the events that are mediated by IGF-1 receptor transactivation are now becoming better understood. For instance, we now know that the IGF-1 receptor is required for activation of PI3-kinase in response to angiotensin II. Second, we have identified CREB as a critical factor for re-entry of cells into the cell cycle. Third, inhibitors capable of interfering with the function of these mediators are being tested for their ability to prevent restenosis, and thus restricting the formation of an arterial blockage in response to balloon angioplasty or bypass graft surgery. We recently demonstrated the importance of angiotensin II in restenosis by showing an angiotensin receptor blocker can reduce restenosis in a porcine model of balloon angioplasty. As part of this work we successfully demonstrated that application of an inhibitor of smooth muscle proliferation to the surface of a vessel is one way to prevent formation of lesions in vessels subjected to angioplasty. Based on our findings, we are recommending that compounds exhibiting efficacy be sought and tested using this novel method of administration.
Lifestyle, Naturally-derived Bioactives and Nutrigenomics: The lab has begun to investigate a variety of bioactive molecules to determine their utility in disease treatment. At this moment, we are actively engaged in studies with derivatives from buckwheat, dairy products and wheat. Buckwheat has an ingredient capable of reducing blood sugar levels in type 1 diabetic rats. Conjugated linoleic acid (CLA), which is present in dairy foods and beef, has been found to reverse the adverse effects of obesity. Wheat bran contains material that is capable of decreasing the amount of adipose tissue. In each case, we are intent on identifying, isolating and characterizing the specific agent(s) responsible for these beneficial actions. Future plans include conducting human studies to evaluate their ability to have the same effects. Consequently, we are developing the capacity to perform human studies, primarily in relation to cardiovascular disease. This program is already active for a study of the beneficial effects of pulses/legumes on blood vessel health.
Within this context, we are heading a new initiative to develop molecular tools appropriate for early diagnosis of vascular disease. This program includes the participation of several basic science and clinical researchers, each providing a distinct expertise. Our objective is to identify specific molecular markers of endothelial dysfunction by comparing the genetic profile of a select patient population. This approach is likewise being used with animal models to define the genetic changes that can be used to detect the presence of specific nutrients in the diet and their ability to influence disease. We anticipate nutrigenomics will eventually have a major impact on our ability to monitor and influence lifestyle by indicating what foods and food components have beneficial and detrimental effects on individuals.
Northcott JM, Yeganeh A, Taylor CG, Zahradka P, Wigle JT. (2012) Adipokines and the cardiovascular system: mechanisms mediating health and disease. Can J Physiol Pharmacol.
Mohankumar SK, Taylor CG, Siemens L, Zahradka P. (2012) Acute exposure of L6 myotubes to cis-9, trans-11 and trans-10, cis-12 conjugated linoleic acid isomers stimulates glucose uptake by modulating Ca(2+)/calmodulin-dependent protein kinase II. Int J Biochem Cell Biol.
Baranowski M, Enns J, Blewett H, Yakandawala U, Zahradka P, Taylor CG. (2012) Dietary flaxseed oil reduces adipocyte size, adipose monocyte chemoattractant protein-1 levels and T-cell infiltration in obese, insulin-resistant rats. Cytokine.
Louis XL, Thandapilly SJ, Mohankumar SK, Yu L, Taylor CG, Zahradka P, Netticadan T. (2011) Treatment with low-dose resveratrol reverses cardiac impairment in obese prone but not in obese resistant rats. J Nutr Biochem.
Mohankumar SK, Taylor CG, Zahradka P. (2012) Domain-dependent modulation of insulin-induced AS160 phosphorylation and glucose uptake by Ca2+/calmodulin-dependent protein kinase II in L6 myotubes. Cell Signal.
Declercq V, Taylor CG, Zahradka P. (2012) Isomer-specific effects of conjugated linoleic acid on blood pressure, adipocyte size and function. Br J Nutr.
Enns JE, Taylor CG, Zahradka P. (2011) Variations in Adipokine Genes AdipoQ, Lep, and LepR are Associated with Risk for Obesity-Related Metabolic Disease: The Modulatory Role of Gene-Nutrient Interactions. J Obes.
Thandapilly SJ, Louis XL, Yang T, Stringer DM, Yu L, Zhang S, Wigle J, Kardami E, Zahradka P, Taylor C, Anderson HD, Netticadan T. (2011)
Resveratrol prevents norepinephrine induced hypertrophy in adult rat cardiomyocytes, by activating NO-AMPK pathway. Eur J Pharmacol.
DeClercq V, Taylor CG, Wigle J, Wright B, Tworek L, Zahradka P. (2012) Conjugated linoleic acid improves blood pressure by increasing adiponectin and endothelial nitric oxide synthase activity. J Nutr Biochem.
Louis S, Saward L, Zahradka P. (2011) Both AT₁ and AT₂ receptors mediate proliferation and migration of porcine vascular smooth muscle cells. Am J Physiol Heart Circ Physiol.
Leyva DR, Zahradka P, Ramjiawan B, Guzman R, Aliani M, Pierce GN. (2011) The effect of dietary flaxseed on improving symptoms of cardiovascular disease in patients with peripheral artery disease: rationale and design of the FLAX-PAD randomized controlled trial. Contemp Clin Trials.
Louis SF, Zahradka P. (2010) Vascular smooth muscle cell motility: From migration to invasion. Exp Clin Cardiol.
Perrault R, Wright B, Storie B, Hatherell A, Zahradka P. (2011) Tyrosine kinase-independent activation of extracellular-regulated kinase (ERK) 1/2 by the insulin-like growth factor-1 receptor. Cell Signal.
Dietary t10,c12-CLA but not c9,t11 CLA reduces adipocyte size in the absence of changes in the adipose renin-angiotensin system in fa/fa Zucker rats.
DeClercq V, Zahradka P, Taylor CG.
Lipids. 2010 Nov;45(11):1025-33. Epub 2010 Sep 16.
Modulation of lipid droplet size and lipid droplet proteins by trans-10,cis-12 conjugated linoleic acid parallels improvements in hepatic steatosis in obese, insulin-resistant rats.
Stringer DM, Zahradka P, Declercq VC, Ryz NR, Diakiw R, Burr LL, Xie X, Taylor CG.
Biochim Biophys Acta. 2010 Dec;1801(12):1375-85. Epub 2010 Aug 25.
Biological response of hepatomas to an extract of Fagopyrum esculentum M. (buckwheat) is not mediated by inositols or rutin.
Curran JM, Stringer DM, Wright B, Taylor CG, Przybylski R, Zahradka P.
J Agric Food Chem. 2010 Mar 10;58(5):3197-204.
IGF-1 receptor transactivation mediates Src-dependent cortactin phosphorylation in response to angiotensin II.
Zahradka P, Storie B, Wright B.
Can J Physiol Pharmacol. 2009 Oct;87(10):805-12.
Improved n-3 fatty acid status does not modulate insulin resistance in fa/fa Zucker rats.
Gillam M, Noto A, Zahradka P, Taylor CG.
Prostaglandins Leukot Essent Fatty Acids. 2009 Nov-Dec;81(5-6):331-9. Epub 2009 Oct 28. Erratum in: Prostaglandins Leukot Essent Fatty Acids. 2010 Jan;82(1):61-2.
Vitamin C restores healthy aging in a mouse model for Werner syndrome.
Massip L, Garand C, Paquet ER, Cogger VC, O’Reilly JN, Tworek L, Hatherell A, Taylor CG, Thorin E, Zahradka P, Le Couteur DG, Lebel M.
FASEB J. 2010 Jan;24(1):158-72. Epub 2009 Sep 9.
Dietary trans-10, cis-12 conjugated linoleic acid reduces early glomerular enlargement and elevated renal cyclooxygenase-2 levels in young obese fa/fa zucker rats.
Drury B, Warford-Woolgar LJ, Herchak DJ, Bankovic-Calic N, Crow G, Taylor CG, Zahradka P, Ogborn MR, Aukema HM.
J Nutr. 2009 Feb;139(2):285-90. Epub 2008 Dec 23.
Adipose tissue: the link between obesity and cardiovascular disease.
DeClercq V, Taylor C, Zahradka P.
Cardiovasc Hematol Disord Drug Targets. 2008 Sep;8(3):228-37. Review.
Meta-iodobenzylguanidine, an inhibitor of arginine-dependent mono(ADP-ribosyl)ation, prevents neointimal hyperplasia.
Yau L, Molnar P, Moon MC, Buhay S, Werner JP, Molnar K, Saward L, Del Rizzo D, Zahradka P.
J Pharmacol Exp Ther. 2008 Sep;326(3):717-24. Epub 2008 Jun 3.
Abnormal immune responses in fa/fa Zucker rats and effects of feeding conjugated linoleic acid.
Ruth MR, Taylor CG, Zahradka P, Field CJ.
Obesity (Silver Spring). 2008 Aug;16(8):1770-9. Epub 2008 May 15.
Injury-induced expression of cytokeratins 8 and 18 by vascular smooth muscle cells requires concurrent activation of cytoskeletal and growth factor receptors.
Moon MC, Yau L, Wright B, Zahradka P.
Can J Physiol Pharmacol. 2008 May;86(5):223-31.
Novel role for osteopontin in cardiac fibrosis.
Circ Res. 2008 Feb 15;102(3):270-2. No abstract available.
Dietary zinc attenuates renal lead deposition but metallothionein is not directly involved.
Jamieson JA, Stringer DM, Zahradka P, Taylor CG.
Biometals. 2008 Feb;21(1):29-40. Epub 2007 Mar 28.
Raissa Perrault (M.Sc., Physiology, graduated in 2010)
2008: NSERC Canadian Graduate Scholarship (Master’s) – 2 years
Danielle Stringer (Ph.D. program, Human Nutritional Sciences)
2011: Manitoba Health Research Council Scholarship (Doctoral) – 2 years
2010: Bruce McDonald Award in Clinical Nutrition
2009: Manitoba Health Research Council Scholarship (Doctoral) – 2 years
2007: NSERC Canadian Graduate Scholarship (Doctoral) – 2 years; Manitoba Graduate Scholarship – 4 years; Garson N. Vogel Scholarship in Food and Nutritional Sciences; Manitoba Health Research Council Scholarship (Doctoral) – declined; University of Manitoba Graduate Fellowship (Doctoral) – declined
Suresh Mohankumar (Post-doctoral fellow)
2012: ISSFAL Top New Investigator Award
2010: NSERC-CREATE Food Advancement through Science and Training Scholarship – 3 years
Jennifer Enns (Ph.D. program, Physiology)
2012: Dr. Peter Douglas Brown Graduate Studies Scholarship (awarded by Westgate Mennonite Collegiate, Winnipeg)
2011: Manitoba Health Research Council Scholarship (Doctoral) – declined; NSERC-CREATE Food Advancement through Science and Training Scholarship – 3 years
Azadeh Yeganeh (Ph.D. program, Physiology)
2011: Therapeutic Applications of Functional Foods Symposium Best Poster Presentation Award
Linda Siemens (M.Sc. program, Human Nutritional Sciences)
2012: Manitoba Health Research Council Scholarship (Master’s) – 2 years;
2011: NSERC Canadian Graduate Scholarship (Master’s) – 1 year; University of Manitoba Graduate Fellowship – declined
2009 and 2010: NSERC Undergraduate Student Research Award (summer)
Matthew Hanson (M.Sc. program, Physiology)
2011: NSERC-CREATE Food Advancement through Science and Training Scholarship – 1 year; Functional Foods and Natural Health Products Graduate Research Symposium Best Oral Presentation Award
Natural Sciences and Engineering Research Council – Hormonal mechanisms of gene regulation
Canadian Institutes of Health Research RPP – Modulation of vascular smooth muscle cell phenotype by angiotensin II
Agri-food Research Development Initiative (ARDI) – Effects of CLA isomers on reduction of insulin resistance (Awarded to C.G. Taylor and P. Zahradka)
Natural Sciences and Engineering Research Council – Strategic Grant – Evaluation of insulin-mimetic components of buckwheat (Awarded to C.G. Taylor, P. Zahradka and L. Murphy)
Pulse Canada – Pulse crops improve CV health by promoting adiopkine (Awarded to P. Zahradka, C.G. Taylor and R. Guzman)
Dairy Producers of Canada – Mechanism for modulation of insulin action and obesity by CLA (Awarded to C.G. Taylor and P. Zahradka)
Summer Student Support