• van Breemen, Cornelis

    Titles
    Investigator Emeritus, BC Children's Hospital

    Professor Emeritus, Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia

    Degrees / Designations
    DVM, M.Sc., PhD
    Primary Area of Research
    Brain, Behaviour & Development
    Secondary Area(s) of Research
    Phone
    604-875-2000 ext. 6507
    Fax
    604-875-3120
    Lab Phone
    604-875-3852
    Mailing Address

    BC Children's Hospital Research Institute
    Room 2084
    950 West 28th Avenue
    Vancouver, BC V5Z 4H4

    Affiliate Websites
    Research Areas
    • Cardiovascular pharmacology and pathophysiology
    • Mechanisms in smooth muscle and endothelial cells
    • Calciums imaging
    • Vascular dysfunction in diabetes
    • Marfan syndrome
    Summary

    Our research is devoted to investigation of the events in cells inside the blood vessel walls, which cause cardiovascular disorders, the main cause of death in the developed world. A thin layer of muscle inside the vessel wall governs blood pressure and blood flow along the vessels. This layer consists of smooth muscle cells that contract and relax in response to hormones and stimuli from nerves. Contraction and relaxation of vascular smooth muscle cells are regulated by complex mechanisms inside cells that depend on ion exchange, cellular architecture, and activity of intracellular proteins. Calcium entering the cell through special protein channels plays a central role in regulation of vascular function. We study which proteins regulate calcium influx in vascular cells, and how calcium distribution inside the cell interplays with intracellular structure to regulate vasoconstriction. We also study how diseases such as diabetes or Marfan syndrome affect these orchestrated intracellular mechanisms.

    Current Projects

    Calcium oscillations in vascular smooth muscle
    Ca2+ is a central messenger of smooth muscle function, which regulates both vascular tone and the processes of proliferation, migration and apoptosis. Aberrations in these functions are causally involved in vascular diseases, which are the main causes of death in the developed world. The key to selective Ca2+ regulation of multiple functions lies in the cell's ability to create Ca2+ signals possessing specific temporal and spatial characteristics, which encode differential regulatory information. Ca2+ oscillations are an integral part of "site and function-specific" Ca2+ signaling in smooth muscle cells. These Ca2+ fluctuations are generated by ion channels, exchangers and pumps in the plasma membrane, sarcoplasmic reticulum, and mitochondria, which are strategically clustered in microdomains. In the current project, we study how cell function in norm, neonatal development, aging and disease is related to the temporal and spatial intracellular calcium pattern, the expression and activity of calcium channels, their spatial organization and cellular ultrastructure.

    Cellular mechanisms of vascular dysfunction in human diabetes
    Cardiovascular disorders in diabetes are caused by alterations in cellular mechanisms in endothelial and smooth muscle cells. Unfortunately, at the present time, there is neither the complete understanding of the cellular mechanisms in diabetes, especially in human type 1 (juvenile) and type 2 diabetes, nor specific treatment for cardiovascular disease in patients with diabetes. We study the effect of high glucose concentrations on the human endothelial and smooth muscle cell function (as a model of juvenile diabetes), and changes in signaling pathways in human vascular cells which lead to augmented vasoconstriction and enhanced proliferation. We also investigate spatial and temporal calcium patterns in diabetic vascular cells, alterations in the expression and activity of calcium channels, changes in the cell architecture and extracellular matrix, which contribute to accelerated development of atherosclerosis. This research leads us towards a comprehensive understanding of the cellular mechanisms underlying cardiovascular disease in diabetes, identifying biomarkers and to developing specific therapy for cardiovascular disease and post-surgical care in diabetic patients.

    Vascular dysfunction in Marfan syndrome
    Marfan syndrome (MFS) is an autosomal dominant disorder with mutations in FBN1 gene encoding fibillin-1, the main component of the extracellular microfibrils that is important for formation of elastic fibers. Over 90% of mortality is related to aortic complications in the form of aortic dilatation and rupture. Both smooth muscle and endothelial cells as well as extracellular matrix components could be impaired in MFS. In our project, we use a genetic mouse model of MFS to investigate the cellular mechanisms of the age-dependent disease progression. We intend to characterize the distensibility and elasticity of aortae in vitro, pathologic mechanisms in endothelial and smooth muscle cell signalling, calcium patterns, vessel remodelling, extracellular matrix integrity, cellular ultrastructure, and cell-to-cell interactions. We will monitor disease progression and pathogenesis in the microcirculation in vivo. In addition, we plan to monitor the response to medical therapy. We believe that the study of the biophysical properties and the cellular mechanisms of Marfan syndrome will give new pharmacological targets for treatment of this disease.

    Selected Publications

    Poburko D, Liao CH, van Breemen C, Demaurex N.: Mitochondrial regulation of sarcoplasmic reticulum Ca2+ content in vascular smooth muscle cells. Circ Res. 2009 Jan 2;104(1):104-12.

    Chung AW, Yang HH, Radomski MW, van Breemen C.: Long-term doxycycline is more effective than atenolol to prevent thoracic aortic aneurysm in marfan syndrome through the inhibition of matrix metalloproteinase-2 and -9. Circ Res. 2008 Apr 25;102(8):e73-85.

    Fameli N, van Breemen C, Kuo K-H. A quantitative model for linking Na+/Ca2+ exchange to SERCA during refilling of the sarcoplasmic reticulum to sustain [Ca2+]i oscillations in vascular smooth muscle. Cell Calcium. 2006 (In Press).

    Poburko D, Potter K, van Breemen E, Fameli N, Liao CH, Basset O, Ruegg UT, van Breemen C. Mitochondria buffer NCX-mediated Ca(2+)-entry and limit its diffusion into vascular smooth muscle cells. Cell Calcium. 2006 Jun 26; [Epub ahead of print].

    Chung AYW, Hsiang YN, Matske L, McManus B, van Breemen C, Okon EB. Reduced expression of vascular endothelial growth factor paralleled with the increased angiostatin expression resulting from the upregulated activities of matrix metalloproteinase-2 and -9 in human type 2 diabetic arterial vasculature. Circ Res. 2006; 99(2):140-8.

    van Breemen C, Poburko D, Okon EB. TRP proteins: a new dimension in the treatment of occlusive vascular disease (Invited Editorial). Circ Res. 2006 Mar 3;98(4):446-7.

    Huang J, van Breemen C, Kuo KH, Hove-Madsen L, Tibbits GF. Store-operated Ca2+ entry modulates SR Ca2+ loading in neonatal rabbit cardiac ventricular myocytes. Am J Physiol Cell Physiol. 2006 Jan 18 [Epub ahead of print].

    Okon EB, Chung AW, Rauniyar P, Padilla E, Tejerina T, McManus BM, Luo H, van Breemen C. Compromised Arterial Function in Human Type 2 Diabetic Patients. Diabetes. 2005 Aug; 54(8):2415-2423.

    Lee CH, Kuo KH, Dai J, Leo JM, Seow CY, van Breemen C. Calyculin-A disrupts subplasmalemmal junction and recurring Ca2+ waves in vascular smooth muscle. Cell Calcium. 2005 Jan; 37(1):9-16.

    Poburko D, Kuo KH, Dai J, Lee CH, van Breemen C.  Organellar junctions promote targeted Ca(2+) signalling in smooth muscle: why two membranes are better than one. Trends Pharmacol Sci. 2004 Jan; 25(1):8-15.

    Szado T, Kuo K-H, Bernard-Helary K, Poburko D, Lee CH, Seow C, Ruegg UT, Van Breemen C.  Agonist-induced mitochondrial Ca2+ transients in smooth muscle. Faseb J. 17(1):28-37, 2003.

    Lee CH, Poburko D, Sahota P, Sandhu J, Ruehlamnn DO, van Breemen, C. The mechanism of phenylephrine-mediated [Ca2+)](i) oscillations underlying tonic contraction in the rabbit inferior vena cava.  J Physiol. 534(pt 3):641-50, 2001.

    Grants

    CIHR Operating Grant, Cellular Mechanisms Underlying Vascular Dysfunction & Aortic Aneurysm in Marfan syndrome, 2011

    Honours & Awards
    Research Group Members

    Elena Okon, PhD - Lab manager
    Ada W.-Y Chung, PhD - Postdoctoral fellow
    Nicola Faneli, PhD - Postdoctoral fellow
    Mitra Esfandiarei, PhD - Postdoctoral fellow
    Steyner Cortes, PhD - Visiting assistant professor
    Virginia lemos, PhD - Visiting assistant professor
    Harley Syyong - Graduate (PhD) student
    Minne Dai - Graduate (PhD) student
    Karen Au Yeung - Academic research assistant
    Serge Okon - Academic research assistant