Lipoprotein(a): Cellular Effects and Molecular Mechanisms

Overview

Journal Cholesterol

Date 2012 Sep 20

PMID 22991657

Citations 27

Authors

Kirsten Riches

Karen E Porter

Affiliations

Soon will be listed here.

Abstract

Lipoprotein(a) (Lp(a)) is an independent risk factor for the development of cardiovascular disease (CVD). Indeed, individuals with plasma concentrations >20 mg/dL carry a 2-fold increased risk of developing CVD, accounting for ~25% of the population. Circulating levels of Lp(a) are remarkably resistant to common lipid lowering therapies, and there are currently no robust treatments available for reduction of Lp(a) apart from plasma apheresis, which is costly and labour intensive. The Lp(a) molecule is composed of two parts, an LDL/apoB-100 core and a unique glycoprotein, apolipoprotein(a) (apo(a)), both of which can interact with components of the coagulation cascade, inflammatory pathways, and cells of the blood vessel wall (smooth muscle cells (SMC) and endothelial cells (EC)). Therefore, it is of key importance to determine the molecular pathways by which Lp(a) exerts its influence on the vascular system in order to design therapeutics to target its cellular effects. This paper will summarise the role of Lp(a) in modulating cell behaviour in all aspects of the vascular system including platelets, monocytes, SMC, and EC.

Citing Articles

Lipoprotein(a) and thromboembolism: current state of knowledge and unsolved issues.

Konieczynska M, Natorska J, Zabczyk M, Undas A Arch Med Sci. 2025; 20(6):1770-1783.

PMID: 39967936 PMC: 11831339. DOI: 10.5114/aoms/197357.

Lipoprotein (a)-Related Inflammatory Imbalance: A Novel Horizon for the Development of Atherosclerosis.

Qin T, Ma T, Huang K, Lu S, Zhong J, Li J Curr Atheroscler Rep. 2024; 26(8):383-394.

PMID: 38878139 PMC: 11236888. DOI: 10.1007/s11883-024-01215-5.

Lipid-Derived Biomarkers as Therapeutic Targets for Chronic Coronary Syndrome and Ischemic Stroke: An Updated Narrative Review.

Schreiner T, Ignat B, Grosu C, Costache A, Leon M, Mitu F Medicina (Kaunas). 2024; 60(4).

PMID: 38674207 PMC: 11052465. DOI: 10.3390/medicina60040561.

Targeting Lipoprotein(a): Can RNA Therapeutics Provide the Next Step in the Prevention of Cardiovascular Disease?.

Thau H, Neuber S, Emmert M, Nazari-Shafti T Cardiol Ther. 2024; 13(1):39-67.

PMID: 38381282 PMC: 10899152. DOI: 10.1007/s40119-024-00353-w.

Inverse Association of Lipoprotein(a) on Long-Term Bleeding Risk in Patients with Coronary Heart Disease: Insight from a Multicenter Cohort in Asia.

Wang P, Yuan D, Zhao X, Zhu P, Guo X, Jiang L Thromb Haemost. 2023; 124(7):684-694.

PMID: 37487540 PMC: 11199048. DOI: 10.1055/s-0043-1771188.

References

Cho T, Jung Y, Koschinsky M . 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(45):30503-12. PMC: 2662143. DOI: 10.1074/jbc.M802648200. View

Pokrovsky S, Ezhov M, Ilina L, Afanasieva O, Sinitsyn V, Shiriaev A . Association of lipoprotein(a) excess with early vein graft occlusions in middle-aged men undergoing coronary artery bypass surgery. J Thorac Cardiovasc Surg. 2003; 126(4):1071-5. DOI: 10.1016/s0022-5223(03)00365-9. View

Heimark R, Twardzik D, Schwartz S . Inhibition of endothelial regeneration by type-beta transforming growth factor from platelets. Science. 1986; 233(4768):1078-80. DOI: 10.1126/science.3461562. View

Syrovets T, Thillet J, Chapman M, Simmet T . Lipoprotein(a) is a potent chemoattractant for human peripheral monocytes. Blood. 1997; 90(5):2027-36. View

Lippi G, Targher G . Optimal therapy for reduction of lipoprotein(a). J Clin Pharm Ther. 2012; 37(1):1-3. DOI: 10.1111/j.1365-2710.2011.01244.x. View

Zhao S, Xu D . Oxidized lipoprotein(a) increases the expression of platelet-derived growth factor-B in human umbilical vein endothelial cells. Clin Chim Acta. 2000; 296(1-2):121-33. DOI: 10.1016/s0009-8981(00)00214-x. View

Etingin O, Hajjar D, Hajjar K, HARPEL P, Nachman R . Lipoprotein (a) regulates plasminogen activator inhibitor-1 expression in endothelial cells. A potential mechanism in thrombogenesis. J Biol Chem. 1991; 266(4):2459-65. View

Ren S, Shatadal S, Shen G . Protein kinase C-beta mediates lipoprotein-induced generation of PAI-1 from vascular endothelial cells. Am J Physiol Endocrinol Metab. 2000; 278(4):E656-62. DOI: 10.1152/ajpendo.2000.278.4.E656. View

Boffelli D, Zajchowski D, Yang Z, Lawn R . Estrogen modulation of apolipoprotein(a) expression. Identification of a regulatory element. J Biol Chem. 1999; 274(22):15569-74. DOI: 10.1074/jbc.274.22.15569. View

10.

Yano Y, Seishima M, Tokoro Y, Noma A . Stimulatory effects of lipoprotein(a) and low-density lipoprotein on human umbilical vein endothelial cell migration and proliferation are partially mediated by fibroblast growth factor-2. Biochim Biophys Acta. 1998; 1393(1):26-34. DOI: 10.1016/s0005-2760(98)00052-6. View

11.

Miyata M, Biro S, Kaieda H, Tanaka H . Lipoprotein(a) stimulates the proliferation of cultured human arterial smooth muscle cells through two pathways. FEBS Lett. 1995; 377(3):493-6. DOI: 10.1016/0014-5793(95)01404-7. View

12.

Mackman N . Role of tissue factor in hemostasis, thrombosis, and vascular development. Arterioscler Thromb Vasc Biol. 2004; 24(6):1015-22. DOI: 10.1161/01.ATV.0000130465.23430.74. View

13.

Yano Y, Shimokawa K, Okada Y, Noma A . Immunolocalization of lipoprotein(a) in wounded tissues. J Histochem Cytochem. 1997; 45(4):559-68. DOI: 10.1177/002215549704500408. View

14.

Kojima S, HARPEL P, Rifkin D . Lipoprotein (a) inhibits the generation of transforming growth factor beta: an endogenous inhibitor of smooth muscle cell migration. J Cell Biol. 1991; 113(6):1439-45. PMC: 2289027. DOI: 10.1083/jcb.113.6.1439. View

15.

Nakagami F, Nakagami H, Osako M, Iwabayashi M, Taniyama Y, Doi T . Estrogen attenuates vascular remodeling in Lp(a) transgenic mice. Atherosclerosis. 2010; 211(1):41-7. DOI: 10.1016/j.atherosclerosis.2010.01.016. View

16.

Owens G, Geisterfer A, Yang Y, Komoriya A . Transforming growth factor-beta-induced growth inhibition and cellular hypertrophy in cultured vascular smooth muscle cells. J Cell Biol. 1988; 107(2):771-80. PMC: 2115195. DOI: 10.1083/jcb.107.2.771. View

17.

Etienne-Manneville S, Hall A . Rho GTPases in cell biology. Nature. 2002; 420(6916):629-35. DOI: 10.1038/nature01148. View

18.

Levin E, Miles L, Fless G, Scanu A, Baynham P, Curtiss L . Lipoproteins inhibit the secretion of tissue plasminogen activator from human endothelial cells. Arterioscler Thromb. 1994; 14(3):438-42. DOI: 10.1161/01.atv.14.3.438. View

19.

Haque N, Zhang X, French D, Li J, Poon M, Fallon J . CC chemokine I-309 is the principal monocyte chemoattractant induced by apolipoprotein(a) in human vascular endothelial cells. Circulation. 2000; 102(7):786-92. DOI: 10.1161/01.cir.102.7.786. View

20.

Kagawa A, Azuma H, Akaike M, Kanagawa Y, Matsumoto T . Aspirin reduces apolipoprotein(a) (apo(a)) production in human hepatocytes by suppression of apo(a) gene transcription. J Biol Chem. 1999; 274(48):34111-5. DOI: 10.1074/jbc.274.48.34111. View