Cardiology

ATHEROSCLEROSIS AND VASCULAR BIOLOGY

Brief Description

This research program is focused on the interface between basic and clinical sciences in an effort to better understand the pathogenesis of vascular disease, and in so doing to develop innovative approaches for their prevention and treatment. The program is divided into several distinct components. The first relates to mechanisms of atherogenesis, and focuses mainly on transgenic mouse models of this disorder. The second component focuses on innovative therapeutic strategies for vascular diseases, in particular cell- and gene-based treatments, and represents a major translational research activity extending from “molecules to medicine”. An example of this activity is the Therapeutic Angiogenesis Research Program, which spans fundamental molecular biology to preclinical models and clinical trials. This program has resulted in the launch of the “NORTHERN Trial”, a nation-wide multicenter phase II/III clinical trial led by the University of Toronto, to assess the efficacy of percutaneous intramyocardial delivery of VEGF plasmid DNA in patients with nonrevascularizable coronary disease. A third component of the program relates to pulmonary hypertension, and involves a coordinated research strategy bridging basic models and mechanisms of disease with translational research that is targeted to developing novel cell and gene-based clinical therapies.

Principal Investigators

Recent Original Research Publications

Zhao YD, Campbell AI, Robb M, Ng D, Stewart DJ. Protective role of angiopoietin-1 in experimental pulmonary hypertension. Circ Res. 2003 May 16;92(9):984-91

Mungrue IN, Gros R, You X, Pirani A, Azad A, Csont T, Schulz R, Butany J, Stewart DJ, Husain M. Cardiomyocyte overexpression of iNOS in mice results in peroxynitrite generation, heart block, and sudden death. J Clin Invest. 2002 Mar;109(6):735-43.

You XM, Mungrue IN, Kalair W, Afroze T, Ravi B, Sadi AM, Gros R, Husain M. Conditional expression of a dominant-negative c-Myb in vascular smooth muscle cells inhibits arterial remodeling after injury. Circ Res. 2003 Feb 21;92(3):314-21.

Li C, Cantor WJ, Nili N, Robinson R, Fenkell L, Tran YL, Whittingham HA, Tsui W, Cheema AN, Sparkes JD, Pritzker K, Levy DE, Strauss BH. Arterial repair after stenting and the effects of GM6001, a matrix metalloproteinase inhibitor. J Am Coll Cardiol. 2002 Jun 5;39(11):1852-8.

Teoh H, Zacour M, Wener AD, Gunaratnam L, Ward ME. Increased myofibrillar protein phosphatase-1 activity impairs rat aortic smooth muscle activation after hypoxia. Am J Physiol Heart Circ Physiol. 2003 Apr;284(4):H1182-9.

Leong-Poi H, Christiansen J, Klibanov AL, Kaul S, Lindner JR. Noninvasive assessment of angiogenesis by ultrasound and microbubbles targeted to alpha(v)-integrins. Circulation. 2003 Jan 28;107(3):455-60.

Future Directions

The future plans of the program are to initiate several innovative clinical trials over the course of the next 2-3 years, translating new knowledge in the domain of cardiovascular regenerative science into new clinical therapies. In particular, the first human implantation of a novel biological coronary stent that incorporates humanized antibodies directed toward the capture of circulating endothelial progenitor cells will occur within the year. As well, a cell-based gene therapy trial for severe primary pulmonary hypertension, the first of its kind in the world, is planned to begin in early 2004, and the use of genetically-engineered endothelial progenitor cells in clinical angiogenesis and myogenesis trials will follow shortly thereafter.