Dr. Pawan Singal
Principal Investigator
Cell Pathophysiology, Institute of Cardiovascular Sciences
Professor
Department of Physiology and Pathophysiology, University of Manitoba
Research Focus
There have been significant developments in cardiac care and treatment, and yet many patients who survive a heart attack will subsequently go into heart failure. Is the mishandling of oxygen in the body a contributing factor? When life-sustaining oxygen is improperly handled within a cell, free radicals are created – a new, toxic species that tends to be removed under normal conditions. However, if the body’s natural defenses are lowered, they can be detrimental.
Dr. Singal’s pioneering studies have led the way in understanding how various antioxidants have the potential to prevent or treat the damage associated with free radical induced oxidative stress. Different animal models of heart failure (chronic, subchronic) are utilized to examine cell, sub-cell and molecular changes to understand the pathogenesis of heart failure due to a variety of causes.
Our working hypothesis is that “free-radical based oxidative stress contributes to the pathogenesis of heart failure”.
Why is this work important?
Moving from artificial models of heart failure to animal models, Dr. Singal’s laboratory has determined that following a heart attack, the production of free radicals in the myocardial cells is increased and natural defense mechanisms (antioxidants) become weak. In animals, treatment with various substances that increase antioxidant capacity, can delay the process of heart failure and can fortify defense mechanisms in the myocardium of the heart.
Clearly, the potential for lives saved and quality of lives enhanced in heart patients is enormous. The challenge is to determine the battery of agents that will do the job. No single antioxidant agent will provide a “magic bullet” for combating all free radicals. Different agents will be needed according to whether these radicals lurk on the cell membrane or in any number of compartments within the cell. However, it is possible that the various entry points into heart failure may ultimately merge in some common pathway, and free radicals may be involved at that point. Currently, various substances are being tested in the lab to identify new molecular targets for better management of these patients.
What techniques and equipment are used in this laboratory?
We create different animal models of heart failure. We have the techniques as well as necessary tools to induce heart failure in rats due to pressure overload (i.e. uncontrolled hypertension), myocardial infarction (i.e. loss of heart muscle due to a heart attack) and drug-induced heart failure (e.g. anti-cancer drug, adriamycin). Cardiovascular function of these animals is assessed invasively (cardiac catheterization) or non-invasively (echocardiography).
Heart function is also studied in isolated hearts. Isolated myocytes are used in primary cultures for the study of oxidative stress, antioxidants, subcellular and molecular functions. Different agents are used to mitigate or prevent the progression of heart failure.
About Dr. Pawan K. Singal
Dr. Singal, Professor of Physiology, University of Manitoba, directed the Institute of Cardiovascular Sciences from 2007-2017.
After 3 years in Saskatoon, Canada, as a Postdoctoral Fellow of the Medical Research Council, Dr. Singal joined the Physiology & Pathophysiology Department at the College of Medicine, University of Manitoba, as a lecturer, rose through the ranks and has been a Professor since 1990. He served as Associate Dean for the Faculty of Graduate Studies, University of Manitoba. He is also holder of the Naranjan S. Dhalla Chair established by the St. Boniface Hospital Foundation. Internationally known for his work on oxidative stress and heart failure, Dr. Singal has made significant contributions in the understanding of the sequelae of heart failure. He has published 285 papers, has co-edited 31 books and trained more than 100 students, fellows and visiting scientists. He has received more than 90 national and international recognitions. The University of Manitoba has established an award in his name called ‘Pawan K. Singal Award for Graduate Students in Cardiovascular Sciences’. His name has been added to the Wall of Fame in the University Center at the University of Manitoba recognizing his outstanding teaching skills and research.
Academics
- M.Sc. (Biophysics), Panjab Univ., 1970
- Ph.D. (Physiology), Univ. of Alberta, 1974
- D.Sc., Panjab Univ., 1995
- Postdoctoral Fellow (Physiology), Univ. of Saskatchewan, 1974-77
- Research Associate (Physiology), Univ. of Manitoba, 1977-78
- Lecturer (Physiology), Univ. of Manitoba, 1979-82
- Assistant Professor (Physiology), Univ. of Manitoba, 1982-86
- Associate Professor (Physiology), Univ. of Manitoba, 1986-90
- Professor (Physiology), Univ. of Manitoba, 1990-present
- Staff Scientist, St. Boniface Hospital, 1987-present
- Associate Dean (Academic) Faculty of Graduate Studies, 2000-03
- Director, Institute of Cardiovascular Sciences, 2007-17
Research Interests
Dr. Singal’s laboratory initiated and has continued interest in describing the role of oxidative stress in heart cell pathophysiology. For this purpose, he employs three different animal models of congestive heart failure subsequent to: doxorubicin-induced cardiomyopathy, myocardial infarction and a chronic pressure overload. Dr. Singal proposed that cardiac dilation may be due to a relative increase in the production of free radicals and lipid peroxides as well as a decrease in the “antioxidant reserve.” This hypothesis has been proven by different hemodynamic, molecular biology and histological approaches. Changes in non-enzymatic antioxidants, such as vitamin A and E, are also being characterized to fully understand the oxidative stress changes and their consequences. A major breakthrough in the safe use of the anticancer drug, doxorubicin was achieved in the experimental model developed and reported in the past. More recently, the lab is also focused on investigating to mitigate the cardiotoxic side effects of Herceptin – another anticancer drug in use for breast cancer patients. This research may significantly change/improve therapeutic approaches in the treatment of cancer patients.
For more information, please contact:
Dr. Pawan K. Singal
Institute of Cardiovascular Sciences
St. Boniface Hospital Research
R3022, 351 Taché Avenue
Winnipeg, MB R2H 2A6 Canada
Tel. (204) 235-3416
Fax. (204) 233-6723
Email. psingal@sbrc.ca
In Detail
When good oxygen goes bad
There have been significant developments in cardiac care and treatment, and yet many patients who survive a heart attack will subsequently go into heart failure. Is the mishandling of oxygen in the body a contributing factor? When life-sustaining oxygen is improperly handled within a cell, free radicals are created – a new, toxic species that tends to be removed in the normal scheme of things. However, if the body’s natural defenses are lowered, they can wreak havoc. Not only are free radicals nasty, they’re tricky as well. Dr. Singal describes radicals as “hiding, like rats, in different parts of the cells.” Different agents are needed to attack them in different places.
Dr. Singal’s pioneering studies have led the way in understanding how various antioxidants have the potential to prevent or treat the damage associated with free radical induced oxidative stress.
The Therapeutic Potential of Antioxidants
After almost 20 years of study, Dr. Singal probably understands free radicals better than anyone in the world does. His hypothesis: free-radical based oxidative stress contributes to the pathogenesis of heart failure.
Moving from artificial models of heart failure to animal models, his laboratory has determined that following a heart attack, the production of free radicals in the myocardial cells is increased and natural defense mechanisms (antioxidants) become weak. In animals, treatment with various substances that increase antioxidant capacity, such as vitamin E and various drugs, can delay the process of heart failure and can fortify defense mechanisms in the myocardium of the heart.
Clearly, the potential for lives saved and quality of lives enhanced in heart patients is enormous. The challenge is to determine the battery of agents that will do the job. No single antioxidant agent will provide a “magic bullet” for combating all free radicals. Different agents will be needed according to whether the radicals lurk on the cell membrane or in any number of compartments within the cell. Currently, various substances are being tested in the lab to determine their effectiveness.
Implications for Cancer Treatment
Among the treatments available for cancer patients is an anti-tumor drug called adriamycin. Some 80% of cancers respond to this drug, making it perhaps the most effective treatment available. But soon after its introduction, a deadly side effect became apparent, and that was congestive heart failure. Finding a solution was a challenge Dr. Singal couldn’t resist.
Working with animal models of adriamycin-induced heart failure, his laboratory worked to understand what happens pathologically and histologically to the cell structure during this process. The finding was that the drug increases the production of free radicals and reduces the defense mechanisms against free radicals – a fatal combination leading to heart failure.
The next step was to study the effects of different antioxidants in combating the negative effects of the adriamycin. Eventually, an existing drug, probucol, was discovered to reverse the negative effects leading to heart failure without diluting the anti-cancer properties of the treatment.
This research is now ready to proceed to clinical trials. If human patients respond in the same way as the animal models have, it will have dramatic implications for the successful treatment of a wide range of cancers.
Finding the Common Pathway
To date, only heart failure following myocardial infarction and drug-induced heart failure have been studied, and there are many different instigators which remain to be investigated. However, it is possible that the various entry points into heart failure may ultimately merge in some common pathway, and free radicals may be involved at that point.
Representative Publications
1. Singal, P.K. and Iliskovic, N. Doxorubicin-induced cardiomyopathy. N. Engl. J. Med. 339: 900-905, 1998.
2. Dhingra, S., Sharma, A.K. Arora, R.C., Slezak, J. and Singal, P.K. IL-10 attenuates TNF-α-induced NFκB pathway activation and cardiomyocyte apoptosis. Cardiovas. Res. 82: 59-66, 2009.
3. Khaper, N., Bryan, S., Dhingra, S., Singal, R., Bajaj, A., Pathak, C. and Singal, P.K. Targeting the vicious inflammation-oxidative stress cycle for the management of heart failure. Anti. Redox Signal. 13: 1033-1049, 2010.
4. Dhingra, S., Bagchi, A.K., Ludke, A.L., Sharma, A.K., and Singal, P.K. Akt regulates IL-10 mediated suppression of TNF-α induced cardiomyocyte apoptosis by upregulating Stat3 phosphorylation. PLOS One 6: e25009, 1-9, 2011.
Mario Toppo Distinguished Scientist Award, Association of Scientists of Indian Origin in America, Presented at FASEB Meeting, Washington, D.C., April 19, 1999.
Pawan K. Singal Graduate Student Fellowship in Cardiovascular Sciences: University of Manitoba established this award in 2002.
The Golden Jubilee Medal of Queen Elizabeth II, 2002.
University of Alberta Alumni Association Honour Award, University of Alberta Alumni Association, September 2006.
Big Heart Award, Manitoba Heart and Stroke Foundation, For Outstanding Contributions as a Research Builder, October, 2006.
Media
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