Highlights
- •Lipoprotein(a) exerts pro-inflammatory effects on endothelial cells, monocytes and macrophages.
- •Oxidized phospholipids bound to apolipoprotein(a) drive Lp(a)-induced inflammation.
- •Lipoprotein(a) levels are influenced by inflammatory stimuli.
- •Lipoprotein(a) levels are influenced by anti-inflammatory treatment.
- •Pharmacological Lp(a) decrease may lead to partial decrease in inflammatory burden.
Abstract
The role of lipoprotein(a) (Lp[a]) as a significant and possibly causal cardiovascular
disease (CVD) risk factor has been well established. Many studies, mostly experimental,
have supported inflammation as a mediator of Lp(a)-induced increase in CVD risk. Lp(a),
mainly through oxidized phospholipids bound to its apolipoprotein(a) part, leads to
monocyte activation and endothelial dysfunction. The relationship between Lp(a) and
inflammation is bidirectional as Lp(a) levels, besides being associated with inflammatory
properties, are regulated by inflammatory stimuli or anti-inflammatory treatment.
Reduction of Lp(a) concentration, especially by potent siRNA agents, contributes to
partial reversion of the Lp(a) related inflammatory profile. This review aims to present
the current pathophysiological and clinical evidence of the relationship between Lp(a)
and inflammation.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Journal of Clinical LipidologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Lipoprotein (a) and 10-year cardiovascular disease incidence in apparently healthy individuals: a sex-based sensitivity analysis from ATTICA cohort study.Angiology. 2019; 70: 819-829
- Structure, function, and genetics of lipoprotein (a).J Lipid Res. 2016; 57: 1339-1359
- Genetically elevated lipoprotein(a) and increased risk of myocardial infarction.JAMA. 2009; 301: 2331-2339
- Lipoprotein(a) reduction in persons with cardiovascular disease.N Engl J Med. 2020; 382: 244-255
- ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk.Atherosclerosis. 2019; 290: 140-205
- Extreme lipoprotein(a) levels and improved cardiovascular risk prediction.J Am Coll Cardiol. 2013; 61: 1146-1156
- Inflammatory cytokines in atherosclerosis: current therapeutic approaches.Eur Heart J. 2016; 37: 1723-1732
- Lipoprotein(a): an underestimated inflammatory mastermind.Atherosclerosis. 2022; 349: 101-109
- How common is residual inflammatory risk?.Circ Res. 2017; 120: 617-619
- Atherogenic lipoprotein(a) increases vascular glycolysis, thereby facilitating inflammation and leukocyte extravasation.Circ Res. 2020; 126: 1346-1359
- Convergent evolution of apolipoprotein(a) in primates and hedgehog.Proc Natl Acad Sci U S A. 1997; 94: 11992-11997
- The number of kringle IV repeats 3-10 is invariable in the human apo(a) gene.Gene. 1998; 208: 253-258
- Apolipoprotein(a), through its strong lysine-binding site in KIV(10′), mediates increased endothelial cell contraction and permeability via a Rho/Rho kinase/MYPT1-dependent pathway.J Biol Chem. 2008; 283: 30503-30512
- Determinants of binding of oxidized phospholipids on apolipoprotein (a) and lipoprotein (a).J Lipid Res. 2013; 54: 2815-2830
- Identification of the cysteine residue in apolipoprotein(a) that mediates extracellular coupling with apolipoprotein B-100.J Biol Chem. 1993; 268: 19819-19825
- Oxidized phospholipids: from molecular properties to disease.Biochim Biophys Acta. 2007; 1772: 718-736
- A novel function of lipoprotein [a] as a preferential carrier of oxidized phospholipids in human plasma.J Lipid Res. 2008; 49: 2230-2239
- Activation of TLR2 and TLR4 by minimally modified low-density lipoprotein in human macrophages and monocytes triggers the inflammatory response.Hum Immunol. 2010; 71: 737-744
- Oxidized phospholipid modification of lipoprotein(a): epidemiology, biochemistry and pathophysiology.Atherosclerosis. 2022; 349: 92-100
- Oxidized phospholipids on lipoprotein(a) elicit arterial wall inflammation and an inflammatory monocyte response in humans.Circulation. 2016; 134: 611-624
- Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease.N Engl J Med. 2005; 353: 46-57
- Oxidized phospholipids predict the presence and progression of carotid and femoral atherosclerosis and symptomatic cardiovascular disease: five-year prospective results from the Bruneck study.J Am Coll Cardiol. 2006; 47: 2219-2228
- Oxidized phospholipids, lipoprotein(a), lipoprotein-associated phospholipase A2 activity, and 10-year cardiovascular outcomes: prospective results from the Bruneck study.Arterioscler Thromb Vasc Biol. 2007; 27: 1788-1795
- Oxidation-specific biomarkers and risk of peripheral artery disease.J Am Coll Cardiol. 2013; 61: 2169-2179
- Oxidation-specific biomarkers, prospective 15-year cardiovascular and stroke outcomes, and net reclassification of cardiovascular events.J Am Coll Cardiol. 2012; 60: 2218-2229
- Oxidized phospholipids on apolipoprotein B-100 and recurrent ischemic events following stroke or transient ischemic attack.J Am Coll Cardiol. 2017; 69: 147-158
- Relationship of oxidized phospholipids on apolipoprotein B-100 to cardiovascular outcomes in patients treated with intensive versus moderate atorvastatin therapy: the TNT trial.J Am Coll Cardiol. 2015; 65: 1286-1295
- Oxidized phospholipids on apolipoprotein B-100 versus plasminogen and risk of coronary heart disease in the PROCARDIS study.Atherosclerosis. 2022; 354: 15-22
- Effect of therapeutic interventions on oxidized phospholipids on apolipoprotein B100 and lipoprotein(a).J Clin Lipidol. 2016; 10: 594-603
- Prevalence and influence of LPA gene variants and isoform size on the Lp(a)-lowering effect of pelacarsen.Atherosclerosis. 2021; 324: 102-108
- Pro-inflammatory interleukin-1 genotypes potentiate the risk of coronary artery disease and cardiovascular events mediated by oxidized phospholipids and lipoprotein(a).J Am Coll Cardiol. 2014; 63: 1724-1734
- Interleukin-1 genotypes modulate the long-term effect of lipoprotein(a) on cardiovascular events: The Ioannina Study.J Clin Lipidol. 2018; 12: 338-347
- Mechanistic insights into Lp(a)-induced IL-8 expression: a role for oxidized phospholipid modification of apo(a).J Lipid Res. 2015; 56: 2273-2285
- Stimulation of interleukin-8 production in human THP-1 macrophages by apolipoprotein(a). Evidence for a critical involvement of elements in its C-terminal domain.J Biol Chem. 2001; 276: 46864-46869
- Lipoprotein (a) downregulates lysosomal acid lipase and induces interleukin-6 in human blood monocytes.Biochim Biophys Acta. 2003; 1642: 25-31
- Potent lipoprotein(a) lowering following apolipoprotein(a) antisense treatment reduces the pro-inflammatory activation of circulating monocytes in patients with elevated lipoprotein(a).Eur Heart J. 2020; 41: 2262-2271
- Short-term regulation of hematopoiesis by lipoprotein(a) results in the production of pro-inflammatory monocytes.Int J Cardiol. 2020; 315: 81-85
- Atherogenic lipids and lipoproteins trigger CD36-TLR2-dependent apoptosis in macrophages undergoing endoplasmic reticulum stress.Cell Metab. 2010; 12: 467-482
- Expression of adhesion molecules by lp(a): a potential novel mechanism for its atherogenicity.FASEB J. 1998; 12: 1765-1776
- Expression of vascular cell adhesion molecule-1 in the aortic tissues of atherosclerotic patients and the associated clinical implications.Exp Ther Med. 2015; 10: 423-428
- Lipoprotein(a) enhances the expression of intercellular adhesion molecule-1 in cultured human umbilical vein endothelial cells.Circulation. 1998; 97: 721-728
- CC chemokine I-309 is the principal monocyte chemoattractant induced by apolipoprotein(a) in human vascular endothelial cells.Circulation. 2000; 102: 786-792
- MCP-1 binds to oxidized LDL and is carried by lipoprotein(a) in human plasma.J Lipid Res. 2013; 54: 1877-1883
- The apolipoprotein(a) component of lipoprotein(a) stimulates actin stress fiber formation and loss of cell-cell contact in cultured endothelial cells.J Biol Chem. 2004; 279: 6526-6533
- Apolipoprotein(a) stimulates nuclear translocation of beta-catenin: a novel pathogenic mechanism for lipoprotein(a).Mol Biol Cell. 2013; 24: 210-221
- IL-6 blockade by monoclonal antibodies inhibits apolipoprotein (a) expression and lipoprotein (a) synthesis in humans.J Lipid Res. 2015; 56: 1034-1042
- Detecting human coronary inflammation by imaging perivascular fat.Sci Transl Med. 2017; 9
- Persistent arterial wall inflammation in patients with elevated lipoprotein(a) despite strong low-density lipoprotein cholesterol reduction by proprotein convertase subtilisin/kexin type 9 antibody treatment.Eur Heart J. 2019; 40: 2775-2781
- Specific Lp(a) apheresis: a tool to prove lipoprotein(a) atherogenicity.Atheroscler Suppl. 2017; 30: 166-173
- Lp(a) lipoprotein and lipids in patients with rheumatoid arthritis: serum levels and relationship to inflammation.Rheumatol Int. 2005; 25: 241-245
- Lipoprotein(a) levels in systemic lupus erythematosus.J Rheumatol. 1994; 21: 220-223
- Increased levels of lipoprotein (a) in Crohn's disease: a relation to thrombosis?.Eur J Gastroenterol Hepatol. 2001; 13: 1415-1419
- Transient changes of serum lipoprotein(a) as an acute phase protein.Atherosclerosis. 1989; 78: 145-150
- Lipoprotein(a), lipids and proinflammatory cytokines in patients undergoing major abdominal surgery.Br J Surg. 2006; 93: 347-353
- Lipoprotein(a) and SARS-CoV-2 infections: susceptibility to infections, ischemic heart disease and thromboembolic events.J Intern Med. 2022; 291: 101-107
- The role of lipoprotein(a) in coronavirus disease 2019 (COVID-19) with relation to development of severe acute kidney injury.J Thromb Thrombolysis. 2021; 53: 581-585
- Lipoprotein(a), venous thromboembolism and COVID-19: a pilot study.Atherosclerosis. 2021; 341: 43-49
- Serum levels of lipoprotein(a) and E-selectin are reduced in rheumatoid arthritis patients treated with methotrexate or methotrexate in combination with TNF-alpha-inhibitor.Clin Exp Rheumatol. 2013; 31: 415-421
- Lipoprotein(a) concentrations in rheumatoid arthritis on biologic therapy: results from the CARdiovascular in rheuMAtology study project.J Clin Lipidol. 2017; 11 (e3): 749-756
- Effect of interleukin-6 receptor blockade on surrogates of vascular risk in rheumatoid arthritis: MEASURE, a randomised, placebo-controlled study.Ann Rheum Dis. 2015; 74: 694-702
- Effects of inhibition of interleukin-6 signalling on insulin sensitivity and lipoprotein (a) levels in human subjects with rheumatoid diseases.PLoS One. 2010; 5: e14328
- Sarilumab and adalimumab differential effects on bone remodelling and cardiovascular risk biomarkers, and predictions of treatment outcomes.Arthritis Res Ther. 2020; 22: 70
Article info
Publication history
Published online: October 19, 2022
Accepted:
October 12,
2022
Received:
April 13,
2022
Identification
Copyright
© 2022 National Lipid Association. Published by Elsevier Inc. All rights reserved.
