Heart Failure, Prostaglandins, and DNA Repair

THE LISTER AND PETERS PRIZES IN RESEARCH

Barry Rubin

Barry Rubin, Medical Director of the Peter Munk Cardiac Centre, is also Head of the Division of Vascular Surgery at University Health Network. He received his MD degree from McGill University and his General and Vascular training at the University of Toronto, completing a PhD in experimental medicine in the Surgeon Scientist Program. The only Wylie Scholar in Academic Vascular Surgery from outside the United States, he has been funded continuously by CIHR for 14 years. He and his wife, Penny have 3 children (See Surgical Spotlight Winter 2008).

He opened with a fascinating discussion of the Calumny of Appelles, a satirical painting by Sandro Boticelli, painted in 1494. The painting shows King Midas surrounded by advisors, Suspicion and Ignorance. Calumny (or slander), dragging an unidentified man by the hair is approaching the King, led by Envy, and attended by Deceit and Fraud. In the distance is Truth, being gazed at menacingly by Penitence. Barry told us that at the beginning of his research career, he felt like the young man being dragged by the hair, in pursuit of truth but surrounded by uncertainty.

He then noted that his success in research was attributable in large part to his mentors, Paul Walker and Wayne Johnston, and his longtime colleague, Tom Lindsay. He then presented a challenging narrative about the molecular regulation of cardiac myocyte growth by prostaglandins. Prostaglandin E2 (PGE2) is critical in the evolution of cardiac injury following myocardial infarction. The final step in PGE2 biosynthesis is catalyzed by an enzyme called mPGES-1. Barry showed that mice which lack mPGES-1 have lower levels of PGE2 and worse left ventricular function after coronary artery ligation. Selectively deleting mPGES-1 in white blood cells, through the use of chimeric mice, also led to worse left systolic and diastolic function after myocardial infarction. This is the first demonstration that an enzyme that controls prostaglandin biosynthesis by white blood cells can modulate the way the heart repairs itself after a heart attack. This body of work has direct clinical implications, as the millions of patients that take an inhibitor of cyclo- oxygenase-2 will be candidates to take inhibitors of mPGES-1, which are currently in clinical trials. Barry closed by acknowledging his network of collaborators in Stockholm, Frankfurt, Boston, Seattle and Toronto, and dedicated his presentation to Drs. Helmut Schmidt (Frankfurt) and Shafie Fazel (Toronto).

The George Armstrong Peter prize for 2010 was awarded to Subodh Verma. Previous winners include William Gallie, Frederick Banting and Charles Tator among others. Subodh received his MSc and PhD from the University of British Columbia and his MD from Calgary. He trained in Cardiac Surgery at the University of Toronto while maintaining an extremely prolific research program. His research has produced over 190 peer-reviewed articles and he is the Canada Research Chair in Atherosclerosis. This year, Subodh was presented with the Howard Morgan Award from the International Academy of Cardiovascular Sciences, listed as one of Canada's Top 40 under 40 (http://www.theglobeandmail.com/report-on-business/managing/top-40-under-40-2009/subodh-verma-39-ontario/article1591369/) and simultaneously placed on the India Abroad Power List. His commitment to nurturing the next generation is evidenced by the 2010 Silver Shovel Award (excellence in overall clinical teaching as voted by the University of Toronto medical students), his fervent efforts to bring to life the St Michael's Li Ka Shing Knowledge Institute-King Saud University collaborative partnership and the recent achievements of his trainees at the annual conferences of the American Association for Thoracic Surgery (2010 C. Walton Lillehei Resident Forum winner - Bobby Yanagawa (Cardiac Surgery resident)), the American Heart Association (2010 Best Basic Cardiovascular Sciences Presentation winner - Young Kim (Cardiology resident), 2009 Vivien Thomas Young Investigator Award winner - Krishna Singh (Postdoctoral Fellow)) and the American College of Cardiology 2009 Young Investigator Award finalist - Praphulla Shukla (Postdoctoral Fellow)).

Subodh thanked Richard Wiesel, Ren-Ke Li, Tirone David, and David Latter for affording him the opportunity to pursue his academic interests throughout his Cardiac Surgery residency. He also expressed his gratitude to his surgeon partners at St Michael's and Surgeonin- Chief, Ori Rotstein, who collectively made it possible for him to balance a productive research program with the demands of an active clinical practice.

Subodh presented recent findings from his laboratory linking the breast cancer gene BRCA1 to cardiovascular disease which has culminated in the successful filing of a U.S. provisional patent. In brief, BRCA1 is a genomewide gatekeeper of DNA repair that has been widely associated with breast, ovarian, and pancreatic cancer. Subodh's "outside-the-box" line of investigation was conceived after Bill Stanford (IBBME) described to him the high incidence of premature heart failure-associated deaths in a colony of Nbr1 (neighbor of BRCA1 gene) mouse mutants.

Subodh Verma with his son, Raj Subhash and his daughter, Meena

Measurements of BRCA1 in the heart were initiated and found to be very low in the naïve state, but there were dramatic increases after induction of myocardial infarction (MI). To definitively identify a potential role for BRCA1 in cardiac physiology/pathology, Subodh generated mice that had one or both copies of the BRCA1 allele specifically deleted in cardiomyocytes. Compared to the control mice, these animals exhibited a higher incidence of ventricular rupture, impaired ventricular function, extensive wall thinning and greater mortality post-MI. Noteworthy, these are features reminiscent of a human ischemic cardiomyopathic phenotype. From a mechanistic standpoint, Subodh's team went on to discover that the adverse cardiac phenotype observed is p53-dependent and involves in part elevated apoptosis and reduced repair of DNA double-strand breaks. That the same unfavourable cardiac pathology was documented in cardiomyocyte - specific BRCA1 knockout mice following treatment with the cardiotoxic anthracyclin doxorubicin lends credence to the robustness of the notion that BRCA1 is cardioprotective. Work on three models of human cardiac ischemia - atrial biopsies obtained before and after initiation of cardiopulmonary bypass and aortic cross clamping, ventricular samples from patients with normal coronary arteries undergoing valvular surgery and from those having coronary artery bypass graft surgeries, and human fetal cardiomyocytes subjected to (non-)ischemic conditions - has revealed that BRCA1 levels are significantly higher in the ischemic groups thereby cementing the clinical relevance and translational potential of this work. Further support stems from recently collected results indicating that derangements in BRCA1 expression and/or bioavailability may resultantly alter substrate metabolism ensuing in an energy starved heart and predisposition to ischemic and non-ischemic heart failure.

The developing picture of the role of BRCA1 in the heart is in brief: acute coronary syndrome causes cardiac ischemia which leads to impaired repair of DNA double-strand breaks and increased apoptosis which can result in late heart failure and potentially cardiac death. Accordingly, the clinical implications are that BRCA1 mutation carriers and their families may be at a previously unrecognized risk of heart failure. This is especially thought-provoking since BRCA1 deficiency has recently been associated with a significantly increased risk of non-cancer related death via unidentified mechanisms.

Three arms of research within Subodh's team have subsequently sprouted the idea that BRCA1 and BRCA2 play an important role in other chronic diseases. With regard to endothelial health, in vitro findings support a role for BRCA1 in inhibiting endothelial apoptosis and in improving endothelial function. Evidence from human atherosclerotic samples show markedly attenuated BRCA1 levels in plaque areas and gain-of-function studies suggest that BRCA1-based cell or gene therapy may represent a novel treatment approach for diseases characterized by endothelial dysfunction, such as atherosclerosis. Led by Hwee Teoh, PhD, an Associate Research Scientist, the group has also accumulated extensive data demonstrating that BRCA1 gene therapy not only retards experimental sepsis-associated multiorgan dysfunction but importantly also limits postsepsis mortality. Preliminary results pivoting around BRCA2 have started to surface and promise to open yet another avenue of investigation into the relevance of oncogenes in cardiovascular medicine.

Subodh has recently initiated discussions with oncologists at the H. Lee Moffitt Cancer Center in Florida to spearhead a clinical study aimed at prospectively evaluating cardiovascular risks in patients with BRCA1/2 mutations. This dynamic team together with Steven Narod, the Canada Research Chair in Breast Cancer, is also looking into the potential of retrospectively assessing cardiovascular risks and incidents in existing and ongoing BRCA1/2 patient registries.

When not focusing on his patients and research, Subodh enjoys and guards his down time shared with his two children and who cannot wait for dog sledding season to arrive.

M.M. with notes from Barry Rubin and Subodh Verma