Mariana J. Kaplan, MD

University of Michigan, Ann Arbor, MI

2002 Biomarkers, Cardiovascular System
2012 Cardiovascular System

Mariana J. Kaplan, MD2012: The Study and What it Means for Patients

Linking innate immunity, oxidative stress and dysfunctional lipids in lupus

“Our study lays the groundwork for therapies preventing cardiovascular disease in lupus. We’re building on LRI-funded work showing high-density lipoprotein (HDL), “good cholesterol,” is a risk factor for lupus-related cardiovascular disease. We’re investigating in patients whether inflammation damages HDL, disrupting its protective effects on the heart and blood vessels.”

Summary:
Premature heart disease is the third most common cause of death in young women with lupus. But the reasons why lupus predisposes to cardiovascular disease are not well understood. Earlier LRI-supported work from Drs. Bevra Hahn and Maureen McMahon showed that the blood levels of a modified form of 'good' cholesterol - high-density lipoprotein - are a powerful indicator of cardiovascular risk in lupus patients. We propose that immune abnormalities in the bodies of lupus patients damage the lipoprotein, disrupting its protective effects on the heart and blood vessels. We propose that, in turn, the modified lipoprotein may alter immune responses in lupus. We will test these ideas by looking at whether lupus patients with cardiovascular disease have increased levels of damaged HDL that is no longer protective and how this HDL affects the immune system.

This theory provides a promising new explanation for the link between lupus and cardiovascular disease that has not been investigated before in patients.

If we are correct, new therapies could be developed to restore protective HDL levels in lupus patients and so prevent cardiovascular disease.

Scientific abstract:
SLE is associated with a striking increase in cardiovascular (CV) risk not fully explained by traditional risk factors. Recently identified CV risk factors in SLE include type I IFNs and enhanced levels of proinflammatory HDL. Myeloperoxidase(MPO)-oxidized HDL is a novel biomarker for clinically significant CVD in other patient populations. Preliminary evidence from our group indicates that SLE patients have striking elevations of MPO-oxHDL, and such oxidation impairs the lipoprotein's ability to remove cholesterol from cells rendering the lipoprotein atherogenic. Recent evidence indicates that non-inflammatory HDL can suppress type I IFN responses in activated macrophages. Preliminary work from our group indicates that this is not the case for HDL from lupus patients. These observations link proinflammatory HDL to the induction of innate immunity and type I IFN responses in SLE. We hypothesize that inflammatory dysfunctional HDL will propagate proatherogenic milieu in lupus patients by altering innate immune responses and impairing reverse cholesterol transport. Aims: 1: Determine MPO and MPO-oxidized HDL levels in SLE patients with and without CVD and assess HDL's functional ability and cholesterol efflux capacity. 2: Determine whether HDL proteome is altered in SLE. 3: Examine the role of dysfunctional lupus HDL in the induction of aberrant responses in macrophages.

Previous LRI-Funded Work

With Lupus Research Institute funding, Dr. Kaplan set out to investigate the mechanisms by which blood vessels are damaged in women with lupus and lead to premature vascular disease.

She discovered that some people with lupus appear to get premature atherosclerotic changes due to the rapid death and slow replacement of endothelial cells. These cells, which line the blood vessels and cavities of the heart, normally keep plaques and clots from forming.

“We found that the lupus patients had abnormal vascular function that was impaired to the same extent seen in the heart disease patients – despite the fact that the lupus patients were approximately half the age,” she explained.

Citing research that points to a role for programmed cell death (called “apoptosis”) of white blood cells within tissues (macrophages) in inducing autoimmunity, Dr. Kaplan aims to find out more about this process so that it can be halted.

“We propose that characterizing the apoptotic ligands involved in APC apoptosis could lead into the development of novel therapeutic interventions designed to abrogate or block the onset and/or severity of this disease.” – Dr. Kaplan

Dr. Kaplan has been published widely and also shared these and other results from her LRI-funded work, such as the discovery that poor vascular function in people with lupus is associated with increased levels of a protein that regulates blood clotting, at several international meetings.

Along with the six investigators now working on the topic that the LRI funded her for in 2002, Dr. Kaplan is hopeful that her discoveries will lead to a biomarker to identify people with lupus at risk of cardiovascular disease. She envisions designing therapies to prevent endothelial cell damage and thereby slash the risk for premature atherosclerosis.

Select publications:

Premature vascular damage in systemic lupus erythematosus. Kaplan MJ. Autoimmunity. 2009 Nov;42(7):580-6. Review.

Accelerated macrophage apoptosis induces autoantibody formation and organ damage in systemic lupus erythematosus. Denny MF, Chandaroy P, Killen PD, Caricchio R, Lewis EE, Richardson BC, Lee KD, Gavalchin J, Kaplan MJ. J Immunol. 2006 Feb 15;176(4):2095-104.

Plasminogen activator inhibitor-1 is associated with impaired endothelial function in women with systemic lupus erythematosus. Somers EC, Marder W, Kaplan MJ, Brook RD, McCune WJ. Ann N Y. Acad Sci. 2005 1051:271-80.

Apoptosis in systemic lupus erythematosus. Kaplan MJ. Clin Immunol. 2004 Sep; 112(3):210-8.

Endothelial cell apoptosis in systemic lupus erythematosus: a common pathway for abnormal vascular function and thrombosis propensity. Rajagopalan S, Somers EC, Brook RD, Kehrer C, Pfenninger D, Lewis E, Chakrabarti A, Richardson BC, Shelden E, McCune WJ, Kaplan MJ. Blood. 2004 103(10):3677-83.

Ongoing funding:

In 2005, Dr, Kaplan won $200,000 from the Alliance for Lupus Research grant to further research the findings she made through her LRI grant. And in 2009, she received a $1.5 million grant from the NIH’s National Heart, Lung, and Blood Institute to continue the promising work on mechanisms of premature vascular disease in lupus. Dr. Kaplan was awarded a Novel Research Grant of $300,000 from the LRI in 2012.

Rev. February 2012