Voices from the Cleveland Clinic On Circulating apoA1: A Biomarker for a Proatherogenic Process in the Artery Wall
Curator: Aviva Lev-Ari, PhD, RN
UPDATED on 3/4/2019
People with Diabetes May Be Missing Out on HDL Cardiovascular Protections
Glycation lowers ApoA1 stability, destroys HDL in T2DM
A Cleveland Clinic study for the first time revealed a mechanism that rapidly destroys high-density lipoprotein (HDL) in people with Type 2 diabetes, negating cardiovascular protections of the so-called good cholesterol.
Sangeeta Kashyap, MD, in Cleveland Clinic’s Endocrinology & Metabolism Institute, and co-author Jonathan D. Smith, PhD, the Geoffrey Gund Endowed Chair for Cardiovascular Research in the Department of Cellular & Molecular Medicine in the Lerner Research Institute, and senior author Takhar Kasumov, PhD, adjunct in Gastroenterology and Hepatology at Cleveland Clinic and fulltime faculty at NEOMED, published a clinical research article in The Journal of Clinical Endocrinology & Metabolism.
The study, “Glycation Reduces the Stability of APOAI and Increases HDL Dysfunction in Diet-Controlled Type 2 Diabetes,” looks at the role of hyperglycemia-induced glycation on ApoA1 kinetics and stability in patients with diet-controlled type 2 diabetes mellitus (T2DM).
Derailing ApoA1
The study found that in people with diabetes, glycation of the ApoA1 molecule causes it to degrade three times faster than in a person without diabetes.
“When ApoA1 is destroyed faster, it is not able to perform its main function for reverse cholesterol uptake, which means taking the bad cholesterol and disposing of it,” says study co-author Sangeeta Kashyap, MD. “The bottom line is that it does not just matter how much good cholesterol you have, but how the cholesterol works to protect you. In people with diabetes, good cholesterol does not work normally to protect them from atherosclerotic heart disease.”
From a clinical perspective, Dr. Kashyap says, the data highlights that normal, or even elevated, HDL levels in T2DM does not equate to adequate functionality. Glycation of ApoA1, she says, is a marker for hyperglycemia-induced HDL dysfunction that blunts the anti-atherogenic and anti-oxidant functions of HDL.
These findings were reached using 2H20-metabolic labeling – a novel heavy water-based non-radioactive technique that looks at the kinetics of HDL by measuring the production and destruction of ApoA1. They study also found ApoA1 instability is related to early glycation of lysine on ApoA1 and associated with glycated hemoglobin (HbA1c) levels – a measure of long-term hyperglycemia.
When Good Cholesterol Goes Bad
“The important clinical piece for practitioners is that even if you see normal or high HDL levels, don’t think it’s working in their favor,” Dr. Kashyap says. “If they have high blood sugar, that’s a marker that HDL is not working to protect them from the atherogenic process.
Dr. Kashyap says lowering glucose levels could be a way to restore HDL functionality in people with diabetes. While previous articles theorized that high triglycerides were related to good cholesterol, this study found that HDL functionality is related to ambient glucose levels.
Reversing the Damage
Next steps involve looking at various glucose lowering interventions, including the effects of the diabetic drug Metformin and insulin, to lower glucose levels.
“We’re interested in looking at specific interventions to lower glucose levels to see if these defects are reversible. We believe they are,” Dr. Kashyap says. “This is an early glycation process. If we are able to lower blood sugar levels, we can reverse levels of lysine glycation of ApoAI and restore functionality of HDL.”
SOURCE
NATURE MEDICINE | ARTICLE
An abundant dysfunctional apolipoprotein A1 in human atheroma
Huang Y, DiDonato JA, Levison BS, et al. An abundant dysfunctional apolipoprotein A1 in human atheroma. Nat Med2014; published online December 26, 2014. DOI:10.1038/nm.3459. Abstract
- Ying Huang,
- Joseph A DiDonato,
- Bruce S Levison,
- Dave Schmitt,
- Lin Li,
- Yuping Wu,
- Jennifer Buffa,
- Timothy Kim,
- Gary S Gerstenecker,
- Xiaodong Gu,
- Chandra S Kadiyala,
- Zeneng Wang,
- Miranda K Culley,
- Jennie E Hazen,
- Anthony J DiDonato,
- Xiaoming Fu,
- Stela Z Berisha,
- Daoquan Peng,
- Truc T Nguyen,
- Shaohong Liang,
- Chia-Chi Chuang,
- Leslie Cho,
- Edward F Plow,
- Paul L Fox,
- Valentin Gogonea
- et al.
Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio, USA.
- Ying Huang,
- Joseph A DiDonato,
- Bruce S Levison,
- Dave Schmitt,
- Lin Li,
- Jennifer Buffa,
- Timothy Kim,
- Gary S Gerstenecker,
- Xiaodong Gu,
- Chandra S Kadiyala,
- Zeneng Wang,
- Miranda K Culley,
- Jennie E Hazen,
- Anthony J DiDonato,
- Xiaoming Fu,
- Stela Z Berisha,
- Daoquan Peng,
- Truc T Nguyen,
- Leslie Cho,
- Paul L Fox,
- Valentin Gogonea,
- W H Wilson Tang,
- Jonathan D Smith &
- Stanley L Hazen
-
Department of Mathematics, Cleveland State University, Cleveland, Ohio, USA.
- Yuping Wu
-
Department of Chemistry, Cleveland State University, Cleveland, Ohio, USA.
- Gary S Gerstenecker &
- Valentin Gogonea
-
Cleveland Heart Lab, Cleveland, Ohio, USA.
- Shaohong Liang
-
Department of Pathology, Section on Lipid Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
- Chia-Chi Chuang &
- John S Parks
-
Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio, USA.
- Leslie Cho,
- Edward F Plow,
- W H Wilson Tang,
- Jonathan D Smith &
- Stanley L Hazen
-
Department of Molecular Cardiology, Cleveland Clinic, Cleveland, Ohio, USA.
- Edward F Plow
-
Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
- John S Parks
-
Department of Cardiovascular Medicine, New York University School of Medicine, New York, New York, USA.
- Edward A Fisher
Contributions
Y.H. participated in all laboratory, animal and human studies, assisted in statistical analyses, helped design the experiments and drafted the manuscript. B.S.L., G.S.G., V.G., C.S.K., Z.W. and X.F. assisted with various laboratory and mass spectrometry studies. D.S., J.B., M.K.C., S.Z.B. and C.-C.C. helped perform various animal experiments. J.A.D., D.S., T.K., X.G., M.K.C., J.E.H., A.J.D. and D.P. helped make various bacterial expression clones and produce and purify recombinant proteins used. J.A.D. and S.L. helped with mAb generation and screening. T.K. and T.T.N. helped with ELISA assays. L.L. and Y.W. provided statistical analyses of clinical data. J.A.D., L.C., E.F.P., P.L.F., V.G., W.H.W.T., J.S.P., E.A.F., J.D.S. and S.L.H. provided experimental analysis and expertise. All authors took part in critical review of the manuscript. The project was scientifically conceived and directed by S.L.H.
- Published online 26 January 2014
Recent studies have indicated that high-density lipoproteins (HDLs) and their major structural protein, apolipoprotein A1 (apoA1), recovered from human atheroma are dysfunctional and are extensively oxidized by myeloperoxidase (MPO). In vitro oxidation of either apoA1 or HDL particles by MPO impairs their cholesterol acceptor function. Here, using phage display affinity maturation, we developed a high-affinity monoclonal antibody that specifically recognizes both apoA1 and HDL that have been modified by the MPO-H2O2-Cl− system. An oxindolyl alanine (2-OH-Trp) moiety at Trp72 of apoA1 is the immunogenic epitope. Mutagenesis studies confirmed a critical role for apoA1 Trp72 in MPO-mediated inhibition of the ATP-binding cassette transporter A1 (ABCA1)-dependent cholesterol acceptor activity of apoA1 in vitro and in vivo. ApoA1 containing a 2-OH-Trp72 group (oxTrp72-apoA1) is in low abundance within the circulation but accounts for 20% of the apoA1 in atherosclerosis-laden arteries. OxTrp72-apoA1 recovered from human atheroma or plasma is lipid poor, virtually devoid of cholesterol acceptor activity and demonstrated both a potent proinflammatory activity on endothelial cells and an impaired HDL biogenesis activity in vivo. Elevated oxTrp72-apoA1 levels in subjects presenting to a cardiology clinic (n = 627) were associated with increased cardiovascular disease risk. Circulating oxTrp72-apoA1 levels may serve as a way to monitor a proatherogenic process in the artery wall.
SOURCE
http://www.nature.com/nm/journal/vaop/ncurrent/abs/nm.3459.html
Interpretation of Results Findings in Heartwire
Oxidized, Dysfunctional HDL Evident in Atheroma
January 27, 2014
DRUG & REFERENCE INFORMATION
An assay for oxidized Trp72-apoA1 is expected to be available from Cleveland Heart Lab by the end of the year. What’s exciting about this assay, said Hazen, is that it detects not just a marker, but also a molecule involved in the disease process. If oxidized apoA1 can be measured and ultimately lowered, there is hope that doing so might reduce the risk of cardiovascular disease.The cardiovascular focus on raising HDL-cholesterol levels to prevent clinical events has been hit with disappointments in recent years, with numerous high-profile studies showing that while it’s possible to raise HDL-cholesterol levels with various agents, doing so does not translate into clinical benefit. One of the hypotheses behind such failures, including
- extended-release niacin in AIM-HIGH and HPS-2/THRIVE and
- two cholesterol ester transfer protein (CETP) inhibitors, dalcetrapib and torcetrapib,
has been that despite raising HDL-cholesterol levels, the HDL particle is dysfunctional.
Hazen, along with three coauthors, reports being a coinventor on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics or therapeutics. He is a paid consultant to AstraZeneca, Cleveland Heart Lab, Esperion, Lilly, Liposcience, Merck, Pfizer, Procter & Gamble, and Takeda. He reports research funding from the Cleveland Heart Lab, Liposcience, Procter & Gamble, and Takeda. Finally, Hazen reports the right to receive royalty payments for inventions/discoveries related to cardiovascular diagnostics or therapeutics from the Cleveland Heart Lab, Esperion, Frantz Biomarkers, and Liposcience . Other disclosures for the coauthors are listed in the online version of the paper.
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Other articles on Apo1 and HDL published on this Open Access Online Scientific Journal include the following:
LDL, HDL, TG, ApoA1 and ApoB: Genetic Loci Associated With Plasma Concentration of these Biomarkers – A Genome-Wide Analysis With Replication
Aviva Lev-Ari, PhD, RN
High-Density Lipoprotein (HDL): An Independent Predictor of Endothelial Function & Atherosclerosis, A Modulator, An Agonist, A Biomarker for Cardiovascular Risk
Aviva Lev-Ari, PhD, RN
Voice from the Cleveland Clinic: On the New Lipid Guidelines and On the ACC/AHA Risk Calculator
Aviva Lev-Ari, PhD, RN
Endothelial Dysfunction (release into the circulation of damaged endothelial cells) as A Risk Marker for Ischemia and MI
Larry H Bernstein, MD, FCAP
https://pharmaceuticalintelligence.com/2014/01/12/endothelial-dysfunction-as-risk-marker/
Artherogenesis: Predictor of CVD – the Smaller and Denser LDL Particles
Aviva Lev-Ari, PhD, RN
Fight against Atherosclerotic Cardiovascular Disease: A Biologics not a Small Molecule – Recombinant Human lecithin-cholesterol acyltransferase (rhLCAT) attracted AstraZeneca to acquire AlphaCore
Aviva Lev-Ari, PhD, RN
Cholesteryl Ester Transfer Protein (CETP) Inhibitor: Potential of Anacetrapib to treat Atherosclerosis and CAD
Aviva Lev-Ari, PhD, RN
Hypertriglyceridemia concurrent Hyperlipidemia: Vertical Density Gradient Ultracentrifugation a Better Test to Prevent Undertreatment of High-Risk Cardiac Patients
Aviva Lev-Ari, PhD, RN
High-Density Lipoprotein (HDL): An Independent Predictor of Endothelial Function & Atherosclerosis, A Modulator, An Agonist, A Biomarker for Cardiovascular Risk
Aviva Lev-Ari, PhD, RN
Lp(a) Gene Variant Association
Larry H Bernstein, MD, FCAP
https://pharmaceuticalintelligence.com/2013/03/06/10447/
Synthetic Biology: On Advanced Genome Interpretation for Gene Variants and Pathways: What is the Genetic Base of Atherosclerosis and Loss of Arterial Elasticity with Aging
Aviva Lev-Ari, PhD, RN
Assessing Cardiovascular Disease with Biomarkers
Larry H Bernstein, MD, FCAP
https://pharmaceuticalintelligence.com/2012/12/25/assessing-cardiovascular-disease-with-biomarkers/
Special Considerations in Blood Lipoproteins, Viscosity, Assessment and Treatment
Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN
What is the role of plasma viscosity in hemostasis and vascular disease risk?
Larry H Bernstein, MD and Aviva Lev-Ari, PhD, RN
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