Marlys L. Koschinsky, Professor, Department of Physiology & Pharmacology, Schulich School of Medicine & Dentistry
Before I learned to read, I remember being fascinated by pictures of scientists working in laboratories. My parents had a children’s encyclopedia set called the Golden Book Encyclopedia. I spent countless hours looking at the many illustrations meant to capture young imaginations. Pictured on the front cover of the 4th book in the series was a scientist wearing a white coat and holding up a test tube – I found this picture to be particularly intriguing and I kept coming back to it over and over again, and asking my parents what it was. That was how I first learned what a scientist is. When I began to read, my favourite stories and books were about the lives of medical science researchers - Louis Pasteur, Alexander Fleming, and Jonas Salk, to name just a few. This was the beginning of my career passion and inspiration to be a medical researcher: to one day be a scientist making discoveries in the lab that would help in the fight against disease.
My research focuses primarily on Lipoprotein(a) (Lp(a)), a causal risk factor for coronary heart disease. Lp(a) is very similar to low density lipoprotein (LDL), a particle often referred to as the “bad cholesterol” that is well-established as a risk factor this disease. Elevated levels of plasma Lp(a) have been identified in clinical studies as the single most common genetically-inherited risk factor for coronary heart disease. However, Lp(a) poses challenges for clinical management since levels of this lipoprotein are relatively resistant to lifestyle modification or lipid-lowering drugs, arising from the fact that levels are primarily genetically determined. Hence, Lp(a) has often been referred to as the “really bad cholesterol”.
Lp(a) contains a protein component called apolipoprotein(a) (apo(a)) that confers unique properties to Lp(a) and may contribute to its role in heart disease through a variety of different mechanisms. Apo(a) contains a series of repeated protein structures called kringles. These kringles contain sequences that contribute to Lp(a) size variability, and resemble similar motifs found in the proenzyme plasminogen. Plasminogen’s role in the breakdown of blood clots has prompted speculation that Lp(a), through its apo(a) component, could interfere with this process in the vasculature. Additionally the ability of apo(a) to bind to proinflammatory oxidized phospholipid species increases the ability of Lp(a) to contribute to inflammation in the vessel wall which is in turn a key contributor to the development of atherosclerosis, the underlying cause of heart attacks and strokes.
Generally we are focused on understanding how we can mitigate the risk associated with Lp(a) by either developing strategies to reduce plasma levels, or by preventing the proatheroscerotic effects of this lipoprotein.
How is Lp(a) removed from the circulation?
The catabolism of Lp(a) remains poorly understood although a primary role for the liver in Lp(a) clearance has been identified. This area of research is becoming increasingly important as a possible target for lowering Lp(a) through therapeutic intervention. Recently studies in my laboratory have shown that the LDL receptor may play a role in LDL catabolism, particularly in settings of low LDL levels and elevated LDL receptor number as is seen with a new class of drugs targeting an LDL receptor-degrading protein called PCSK9. In this regard, we have demonstrated that PCSK9 can increase the uptake of Lp(a) by human liver cells; this supports the clinical observations that PCSK9 inhibitors can reduce Lp(a) concentrations by 20-30%. We are currently looking at roles for other candidate hepatocyte receptors in lowering Lp(a); ongoing studies are characterizing a role for sortilin in Lp(a) catabolism.
What is the nature of the oxidized phospholipid modification of apo(a)?
We are interested in determining where on apo(a) that oxidized phosphoplid is added and how this process is regulated. The ultimate goal of our studies is to identify ways to block this modification, thereby reducing the potential proinflammatory role of Lp(a) in coronary heart disease. We will validate our finding in pre-clinical mouse models of atherosclerosis.
How are and where are apo(a) and LDL assembled into Lp(a) particles?
The site of Lp(a) assembly remains unclear. Previous work from our group has shown that apo(a) and LDL-like particles are both produced in the liver but that the covalent linkage between apo(a) and the apoB-100 component of LDL occurs extracellularly. However, the location of initial, lysine-dependent non-covalent interactions remains unknown. Understanding this process will allow us to design novel approaches to lowering plasma Lp(a) through disruption of assembly of the lipoprotein particle.
What is the role of Lp(a) in promotion of thrombosis in heart attacks and strokes?
We having identified regions in apo(a) that are critical for its ability to prevent the breakdown of blood clots. These clots form as a result of rupture of atherosclerotic plaques and block blood flow in heart or brain. However, nobody knows if Lp(a) contributes to heart attacks and strokes through promotion of atherosclerosis or prevention of blood clot breakdown, or both. Using our knowledge of the key regions of apo(a), we can express forms of the protein in mice that are missing these regions to assess whether Lp(a) directly contributes to persistence of blood clots in mice with atherosclerosis.
B.Sc. (Hons), Biology, University of Winnipeg, 1982
Ph.D., Molecular Genetics of Human Ceruloplasmin, University of British Columbia, 1988
Postdoctoral Fellow, Genentech Inc., 1988-1991
Queen’s University Chancellor’s Research Award, 1999
Premier's Research Excellence Award, 1999
Career Investigator of the Heart and Stroke Foundation of Ontario, 2001-2011
Tony Graham Award for Excellence in Board Service – Heart and Stroke Foundation of Ontario, 2012
Boffa M.B., and Koschinsky M.L. Update on lipoprotein (a) as a cardiovascular risk factor and mediator. Curr. Atheroscler. Reports. 115, 360 (2013).
Boffa M.B., and Koschinsky M.L. Screening for and management of elevated Lp(a). Curr. Cardiol. Reports 15, 417 (2013).
Riches K., Franklin L., Maqbool A., Peckham M., Adams M., Bond J., Warburton P., Feric N.T., Koschinsky M.L., O'Regan D.J., Ball S.G., Turner N.A., and Porter K.E. Apolipoprotein(a) acts as a chemorepellent to human vascular smooth muscle cells via integrin αVβ3 and RhoA/ROCK-mediated mechanisms. Int. J. Biochem. Cell Biol. 45, 1776-1783 (2013).
Romagnuolo R., Marcovina S.M., Boffa M.B., and Koschinsky M.L. Inhibition of plasminogen activation by apo(a): role of carboxyl-terminal lysines and identification of inhibitory domains in apo(a). J. Lipid Res. 55, 625-634 (2014).
Koschinsky M.L., and Boffa M.B. Lipoprotein(a) as a therapeutic target in cardiovascular disease. Expert Opin. Ther. Targets 18, 747-757 (2014).
Romagnuolo R., Scipione C., Boffa M.B., Marcovina S.M., Seidah N.G., and Koschinsky M.L. Lipoprotein(a) catabolism is regulated by Proprotein Convertase Subtilisin/Kexin Type 9 through the low density lipoprotein receptor J. Biol. Chem. 290, 11649-62 (2015).
Koschinsky M.L., and Boffa M.B. Lipoprotein(a): an important cardiovascular risk factor and a clinical conundrum. Endocrinol. Metab. Clin. North Am. 43, 949-962 (2015).
Bouchareb R., Mahmut A., Nsaibia M.J., Boulanger M.-C., Dahou A., Lepine J.-L., Laflamme M.-H.., Hadji F., Couture C., Trahan S., Page S., Bosse Y., Pibarot P., Scipione C.A., Koschinsky M.L., Arsenault B.J., Marette A., and Mathieu P. Circulation 132:667-690 (2015).
Komnenov D., Scipione C.A., Bazzi Z.A., Garabon J.J., Koschinsky M.L., and Boffa M.B. (2015) Pro-inflammatory cytokines reduce human TAFI expression via tristetraprolin-mediated mRNA destabilisation and decreased binding of HuR. Thromb Haemost. 114:337-349 (2015).
Scipione C.A., Sayegh S.E., Romagnuolo R., Tsimikas S., Marcovina S.M., Boffa M.B., and Koschinsky M.L. Mechanistic insights into lipoprotein(a)-induced interleukin-8 expression: a role for oxidized phospholipid modification of apolipoprotein(a). J. Lipid Res. in press (2015).
Marlys L. Koschinsky, PhD
Robarts Research Institute