Vascular Inflammation and Metabolism: From Bedside to Bench and Back

Cholesterol accumulation in the arterial wall is a sine qua non for atherosclerosis; however, it is now well accepted that atherosclerosis is driven by a chronic inflammatory process in response to subendothelial lipoprotein retention and involving innate and adaptive immune responses. Similarly, it is now understood that active inflammation in the vessel wall leads to an unstable atherosclerotic plaque, which is as risk for rupture and subsequent myocardial infarction. Likewise, inflammation plays a key role in the myocardium following an ischemic event, and the host immune response can ultimately lead to the destruction of functional cardiac tissue and eventually, heart failure.

Despite our better understanding of how inflammation exacerbates cardiovascular diseases, there has not been a single therapy developed to date that targets inflammation. Moreover, there is an urgent need to identify active sites of inflammation in the artery wall to better risk-stratify patients and identify those who require urgent intervention. 

Goals of the Cluster

We seek to identify novel mechanisms by which inflammation and metabolism drive the development of cardiovascular disease (i.e., in the vessel wall and the myocardium), and to translate these into cutting-edge diagnostic (i.e., biomarker, imaging) and personalized (i.e., microRNA, small molecule) therapies.

Given the expertise of the cluster members, we have identified specific projects that are the focus of our collaborative efforts: 

  • Atherosclerosis regression and plaque stability
  • Biomarkers of inflammatory and unstable plaques
  • Imaging the inflamed atherosclerotic plaque
  • Non-coding RNA and genetic mechanisms of plaque instability
  • Inflammation in the myocardium post-MI
  • Metabolic switching in heart failure
  • Mechanisms driving in-stent restenosis
  • Integration of lipid metabolism and inflammatory responses
  • Diabetic complications in atherosclerosis
  • Interactions between other chronic inflammatory disease and atherosclerosis (i.e., rheumatoid arthritis, etc.) 

Innovation Cluster Scientists

Lead: Katey Rayner, PhD
Co-lead: Ruth McPherson, MD, PhD

Team members at the University of Ottawa Heart Institute:
Rob Beanlands, MD, Patrick Burgon, PhD, Rob deKemp, PhD, Girish Dwivedi, MD, PhD, Benjamin Hibbert, MD, Tom Lagace, PhD, Peter Liu, MD, Lisa Mielnichuk, MD, Terry Ruddy, MD, Alex Stewart, PhD, Erik Suuronen, PhD, Derek So, MD.

Ottawa-based Team members:
Morgan Fullerton, PhD, University of Ottawa
Subash Sad, PhD, University of Ottawa
John Pezacki, PhD, National Research Council
Zemin Yao, PhD, University of Ottawa
Mary-Ellen Harper, PhD, University of Ottawa
Xiaohui Zha, PhD, Ottawa Hospital Research Institute
Alex Sorisky, PhD, Ottawa Hospital Research Institute

Key input is provided by the “GRIP” Group for Research in Inflammation and Pathogenesis (>20 scientists in the Ottawa region). This includes scientists studying inflammation across many disciplines, including infectious disease, metabolism, cardiovascular, autoimmunity, cancer and neuroinflammatory diseases. This engages basic scientists and clinicians from the Faculty of Medicine, TOH, OHRI, CHEO and UOHI. Steering committee: Subash Sad, PhD, Paul MacPherson, MD, PhD, Alex Sorisky, PhD, Zemin Yao, PhD, Andrew Makrigiannis, PhD and Katey Rayner, PhD.

Ongoing Pilot Projects

We have several ongoing pilot projects within the Cluster studying the intersection between inflammation, metabolism and vascular disease: firstly, we are testing novel PET and SPECT imaging tracers for their utility in detecting unstable atherosclerotic plaques in patients with symptomatic and asymptomatic carotid atherosclerosis. Secondly, we are elucidating novel mechanisms that drive coronary disease in patients with chronic conditions such as HIV and arthritis. We employ animal models of disease (mice, rabbits) as well as cellular models of inflammatory activation using primary human and mouse leukocytes. We make use of our state-of-the-art pre-clinical Molecular Imaging Facility as well as our renowned Ruddy Canadian Cardiovascular Genetics Centre.

Innovation Cluster Publications
  1. Zhang L, Chen X, Sharma P, Moon M, Sheftel AD, Dawood F, Nghiem MP, Wu J, Li RK, Gramolini AO, Sorensen PH, Penninger JM, Brumell JH, Liu PP. HACE1-dependent protein degradation provides cardiac protection in response to haemodynamic stress. Nat Commun. 2014 Mar 11;5:3430.

  2. Almontashiri NA, Fan M, Cheng BL, Chen HH, Roberts R, Stewart AF. Interferon-γ activates expression of p15 and p16 regardless of 9p21.3 coronary artery disease risk genotype. J Am Coll Cardiol. 2013 Jan 15;61(2):143-7.

  3. Robinson N, McComb S, Mulligan R, Dudani R, Krishnan L, Sad S. Type I interferon induces necroptosis in macrophages during infection with Salmonella enterica serovar Typhimurium. Nat Immunol. 2012 Oct;13(10):954-62.

  4. Singaravelu R, Chen R, Lyn RK, Jones DM, O’Hara S, Rouleau Y, Cheng J, Srinivasan P, Nasheri N, Russell RS, Tyrrell DL, Pezacki JP. Hepatitis C virus induced up-regulation of microRNA-27: a novel mechanism for hepatic steatosis. Hepatology. 2014 Jan;59(1):98-108.

  5. Croteau E, Renaud JM, Archer C, Klein R, DaSilva JN, Ruddy TD, Beanlands RS, deKemp RA. β2-adrenergic stress evaluation of coronary endothelial-dependent vasodilator function in mice using 11C-acetate micro-PET imaging of myocardial blood flow and oxidative metabolism. EJNMMI Res. 2014 Dec 16;4(1):68.

  6. Blackburn NJ, Sofrenovic T, Kuraitis D, Ahmadi A, McNeill B, Deng C, Rayner KJ, Zhong Z, Ruel M, Suuronen EJ. Timing underpins the benefits associated with injectable collagen biomaterial therapy for the treatment of myocardial infarction. Biomaterials. 2015 Jan;39:182-92.

  7. Hibbert B, Lavoie JR, Ma X, Seibert T, Raizman JE, Simard T, Chen YX, Stewart D, O’Brien ER. Glycogen synthase kinase-3β inhibition augments diabetic endothelial progenitor cell abundance and functionality via cathepsin B: a novel therapeutic opportunity for arterial repair. Diabetes. 2014 Apr;63(4):1410-21.

  8. Huan T, Rong J, Tanriverdi K, Meng Q, Bhattacharya A, McManus DD, Joehanes R, Assimes TL, McPherson R, Samani NJ, Erdmann J, Schunkert H, Courchesne P, Munson PJ, Johnson AD, O’Donnell CJ, Zhang B, Larson MG, Freedman JE, Levy D, Yang X. Dissecting the Roles of MicroRNAs in Coronary Heart Disease via Integrative Genomic Analyses. Arterioscler Thromb Vasc Biol. 2015 Apr;35(4):1011-21.

  9. Rayner KJ, Esau CC, Hussain FN, McDaniel AL, Marshall SM, van Gils JM, Ray TD, Sheedy FJ, Goedeke L, Liu X, Khatsenko OG, Kaimal V, Lees CJ, Fernandez-Hernando C, Fisher EA, Temel RE, Moore KJ. Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides. Nature. 2011 Oct 19;478(7369):404-7.

  10. Rayner KJ, Sheedy FJ, Esau CC, Hussain FN, Temel RE, Parathath S, van Gils JM, Rayner AJ, Chang AN, Suarez Y, Fernandez-Hernando C, Fisher EA, Moore KJ. Antagonism of miR-33 in mice promotes reverse cholesterol transport and regression of atherosclerosis. J Clin Invest. 2011 Jul;121(7):2921-31.

Funding

Members of the Vascular Inflammation & Metabolism Cluster are supported by operating grants from the Canadian Institutes of Health Research (CIHR), the Heart and Stroke Foundation of Canada (HSFC), the Natural Sciences and Engineering Research Council (NSERC), the HIV Network, Genome Canada, and from various partnerships with industry.

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