Dr. Peter Zahradka
– Molecular Physiology

Dr. Peter Zahradka
Principal Investigator, Molecular Physiology
Canadian Centre for Agri-food Research in Health and Medicine

Research Focus

The Molecular Physiology laboratory has a long-standing interest in how blood vessels respond to mechanical injury. Our research on this topic is directed towards understanding the cellular and molecular processes that enable smooth muscle cells to alter their characteristics, thus allowing them to grow and migrate. These properties are important for repairing sections of vessels that have been damaged, but at times the cells continue to divide even after the repair is complete. This results in the formation of lesions that can interfere with blood flow. Since lesion expansion, a process called restenosis, is associated with interventions such as angioplasty and bypass surgery, it can have life threatening consequences. Thus, our research is also intended to help identify new targets suitable for therapeutic prevention of restenosis.

More recently, we have begun to investigate the role of hormones produced by adipose tissue in mediating blood vessel function. These molecules have considerable impact on our day-to-day lives through their ability to influence metabolism and appetite. Furthermore, several of these hormones, also termed adipokines, have been shown to influence the function and characteristics of blood vessels. Consequently, we have begun to study the relationship between adipokine production 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. In particular, we are interested in determining the mechanisms that regulate the production of adipokines that have anti-atherosclerotic activity.

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. As well, we have shown that bioactive compounds derived from plant and animal sources may be applicable via nutritional intervention to the treatment of obesity-derived disease, including atherosclerosis.

What techniques and equipment are used in this laboratory?

Most of our studies are conducted with cell culture models. We have cells that were derived from vascular (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 numerous 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, particularly protein phosphorylation and ADP-ribosylation, 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 enabled us to begin applying genomics to our examination of how nutritional factors influence vascular 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 new Canadian Centre for Agri-food Research in Health and Medicine in 2006. This new research unit, which is focused on the identification and characterization of new bioactives, will employ both animal and human studies to examine efficacy and safety of these molecules. This new position will enable Dr. Zahradka to determine whether nutritional intervention with novel supplements or food will help in the treatment or prevention of cardiovascular disease.

For more information, contact:

Dr. Peter Zahradka
Tel. 204.235.3507
Fax. 204.237.2289
Email. pzahradka@sbrc.ca

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In Detail

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 maintain 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.

Treating Vascular Disease by Targeting Adipokine Production: Pharmaceutical agents provide their health benefits by impeding or augmenting specific cellular processes. Natural compounds present in a food product or 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.

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 PI 3-kinase in response to angiotensin II. Second, we have identified a putative target for CREB that is required for cyclin expression in mitogen-stimulated smooth muscle cells. This molecule is thus critical 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 retenosis, 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. We have therefore assessed other compounds, and an inhibitor of mono-ADP-ribosylation has been shown to also be effective.

Our investigations of smooth muscle cells have also revealed an important role for PPARs (peroxisome proliferator-activated receptors), which are activated by dietary fat, by successfully distinguished the contribution of PPARα and PPARγ to cell migration and proliferation. These studies represent a novel mechanism for integrating signals elicited by both stress (angiotensin II) and metabolic (adiponectin, PPARs) syndromes. Additionally, an activator of PPARα was found to block restenosis in a culture model of this process.

Lifestyle, Naturally-derived Bioactives and Nutrigenomics: This 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) 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 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.

Top

Zahradka, P. (2007) Cardiovascular actions of the peroxisome proliferator-activated receptor-alpha (PPARα) agonist Wy14,643. Cardiovasc. Drug Rev. 25, in press.

Noto, A., Zahradka, P., Yurkova, N., Xie, X., Truong, H., Nitschmann, E., Ogborn, M.R. & Taylor, C.G. (2007) Dietary conjugated linoleic acid (CLA) decreases adipocyte size and favorably modifies adipokine status and insulin sensitivity in obese, insulin-resistant rats. Metabolism in press.

Junaid, A., Moon, M.C., Harding, G.E.J. & Zahradka, P. (2007) Osteopontin localizes to the nucleus of 293 cells and associates with polo-like kinase-1. Am. J. Physiol. 292, C919-C926.

Zahradka, P., Litchie, B., Yurkova, N. & Taylor, C.G. (2006) Peroxisome proliferator-activated receptor α agonists inhibit smooth muscle cell proliferation and migration. J. Pharmacol. Expt. Ther. 317, 651-659.

Zahradka, P., Harding, G., Litchie, B., Thomas, S., Werner, J.P., Wilson, D.P. & Yurkova, N. (2004) Activation of MMP-2 in response to vascular injury is mediated by phosphatidylinositol 3-kinase-dependent expression of MT1-MMP. Am. J. Physiol. 287, H2861-H2870.

NSERC studentships to Vanessa DeClercq & Danielle Stringer

Natural Sciences and Engineering Research Council – Hormonal mechanisms of gene regulation
$32,460

Canadian Institutes of Health Research RPP – Modulation of vascular smooth muscle cell phenotype by angiotensin II
$100,000

Agri-food Research Development Initiative (ARDI) – Effects of CLA isomers on reduction of insulin resistance (Awarded to C.G. Taylor and P. Zahradka)
$70,000

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)
$173,333

Pulse Canada – Pulse crops improve CV health by promoting adiopkine (Awarded to P. Zahradka, C.G. Taylor and R. Guzman)
$123,015

Dairy Producers of Canada – Mechanism for modulation of insulin action and obesity by CLA (Awarded to C.G. Taylor and P. Zahradka)
$76,325

Summer Student Support
$4,081

TOTAL:
$579,214

There are no opportunities available at this time.