Altered Functionality of Lipoprotein(a) Impacts on Angiogenesis in Diabetic Retinopathy

Purpose Diabetic retinopathy (DR) is a complication of type 2 diabetes mellitus (T2DM). Lipoprotein(a) (Lp(a)) contributes to the progression of DR, but how is unclear. In homeostasis of the retinal microvasculature, myeloid-derived pro-angiogenic cells (PACs) also play a pivotal role, and fail to function properly in diabetic conditions. Here, we explored the putative contribution of Lp(a) from patients with T2DM with/without DR and healthy controls on inflammation and angiogenesis of retinal endothelial cells (RECs), and on PAC differentiation. Subsequently, we compared the lipid composition of Lp(a) from patients to that from healthy controls. Methods Lp(a)/LDL obtained from patients and healthy controls were added to TNF-alpha-activated RECs. Expression of VCAM-1/ICAM-1 was measured using flowcytometry. Angiogenesis was determined in REC-pericyte co-cultures stimulated by pro-angiogenic growth factors. PAC differentiation from peripheral blood mononuclear cells was determined by measuring expression of PAC markers. The lipoprotein lipid composition was quantified using detailed lipidomics analysis. Results Lp(a) from patients with DR (DR-Lp(a)) failed to block TNF-alpha-induced expression of VCAM-1/ICAM-1 in REC whereas Lp(a) from healthy controls (healthy control [HC]-Lp(a)) did. DR-Lp(a) increased REC angiogenesis more than HC-Lp(a) did. Lp(a) from patients without DR showed intermediate profiles. HC-Lp(a) reduced the expression of CD16 and CD105 in PAC, but T2DM-Lp(a) did not. Phosphatidylethanolamine content was lower in T2DM-Lp(a) than in HC-Lp(a). Conclusions DR-Lp(a) does not show the anti-inflammatory capacity seen with HC-Lp(a), but increases REC angiogenesis, and affects PAC differentiation less than HC-Lp(a). These functional differences in Lp(a) in T2DM-related retinopathy are associated with alterations in the lipid composition as compared to healthy conditions.

[1]  May E. Montasser,et al.  A lipidome-wide association study of the lipoprotein insulin resistance index , 2020, Lipids in Health and Disease.

[2]  M. Koschinsky,et al.  Atherogenic Lipoprotein(a) Increases Vascular Glycolysis, Thereby Facilitating Inflammation and Leukocyte Extravasation , 2020, Circulation research.

[3]  F. Kronenberg,et al.  Lipoprotein(a) plasma levels are not associated with incident microvascular complications in type 2 diabetes mellitus , 2020, Diabetologia.

[4]  J. Frohlich,et al.  Lipoprotein(a) the Insurgent: A New Insight into the Structure, Function, Metabolism, Pathogenicity, and Medications Affecting Lipoprotein(a) Molecule , 2020, Journal of lipids.

[5]  D. Lynn,et al.  Human DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis , 2019, bioRxiv.

[6]  Christer S. Ejsing,et al.  Lipidomics needs more standardization , 2019, Nature Metabolism.

[7]  M. Al-Omran,et al.  Circulating Pro-Vascular Progenitor Cell Depletion During Type 2 Diabetes , 2018, JACC. Basic to translational science.

[8]  C. Lewis,et al.  Perivascular macrophages in health and disease , 2018, Nature Reviews Immunology.

[9]  A. Rothova,et al.  Three-dimensional tubule formation assay as therapeutic screening model for ocular microvascular disorders , 2018, Eye.

[10]  P. Fort,et al.  Role of Inflammation in Diabetic Retinopathy , 2018, International journal of molecular sciences.

[11]  Alan W. Stitt,et al.  The Vasoreparative Function of Myeloid Angiogenic Cells Is Impaired in Diabetes Through the Induction of IL1β , 2018, Stem cells.

[12]  A. Tselepis.  Oxidized phospholipids and lipoprotein-associated phospholipase A2 as important determinants of Lp(a) functionality and pathophysiological role , 2018, Journal of biomedical research.

[13]  Jennifer K. Sun,et al.  Diabetic retinopathy: current understanding, mechanisms, and treatment strategies. , 2017, JCI insight.

[14]  W. Tu,et al.  Association Between Serum Lipoprotein(a) and Diabetic Retinopathy in Han Chinese Patients With Type 2 Diabetes , 2017, The Journal of clinical endocrinology and metabolism.

[15]  Alan W. Stitt,et al.  The pathology associated with diabetic retinopathy , 2017, Vision Research.

[16]  F. Kronenberg,et al.  Effect of diet-induced weight loss on lipoprotein(a) levels in obese individuals with and without type 2 diabetes , 2017, Diabetologia.

[17]  G. Schmitz,et al.  Lipoprotein(a) and its role in inflammation, atherosclerosis and malignancies , 2017, Clinical Research in Cardiology Supplements.

[18]  L. Joosten,et al.  Oxidized Phospholipids on Lipoprotein(a) Elicit Arterial Wall Inflammation and an Inflammatory Monocyte Response in Humans , 2016, Circulation.

[19]  M. Banach.  Lipoprotein (a)—We Know So Much Yet Still Have Much to Learn … , 2016, Journal of the American Heart Association.

[20]  Jin A. Choi,et al.  Lipoprotein(a) predicts the development of diabetic retinopathy in people with type 2 diabetes mellitus. , 2016, Journal of clinical lipidology.

[21]  F. Kronenberg,et al.  Lipoprotein(a) levels are associated with aortic valve calcification in asymptomatic patients with familial hypercholesterolaemia , 2015, Journal of internal medicine.

[22]  C. Costagliola,et al.  Diabetic Retinopathy: Vascular and Inflammatory Disease , 2015, Journal of diabetes research.

[23]  F. Pileggi,et al.  Lipoprotein (a): Structure, Pathophysiology and Clinical Implications , 2014, Arquivos brasileiros de cardiologia.

[24]  Alan W. Stitt,et al.  The role of immune-related myeloid cells in angiogenesis. , 2013, Immunobiology.

[25]  M. Boffa,et al.  Determinants of binding of oxidized phospholipids on apolipoprotein (a) and lipoprotein (a)1 , 2013, Journal of Lipid Research.

[26]  S. Salomone,et al.  Lipoprotein(a) Serum Levels in Diabetic Patients with Retinopathy , 2013, BioMed research international.

[27]  B. Miller,et al.  Lipidomic analysis of human plasma reveals ether-linked lipids that are elevated in morbidly obese humans compared to lean , 2013, Diabetology & Metabolic Syndrome.

[28]  William E. Dotterweich,et al.  HIV Disease Activity as a Modulator of Lipoprotein(a) and Allele-Specific Apolipoprotein(a) Levels , 2013, Arteriosclerosis, thrombosis, and vascular biology.

[29]  Mohit Chopra,et al.  Pathophysiology of Diabetic Retinopathy , 2013, ISRN ophthalmology.

[30]  M. Boffa,et al.  Apolipoprotein(a) Inhibits In Vitro Tube Formation in Endothelial Cells: Identification of Roles for Kringle V and the Plasminogen Activation System , 2013, PloS one.

[31]  F. Ghanchi,et al.  The Royal College of Ophthalmologists’ clinical guidelines for diabetic retinopathy: a summary , 2013, Eye.

[32]  A. Avogaro,et al.  Endothelial progenitor cells in diabetes mellitus , 2012, BioFactors.

[33]  J. Andersen,et al.  Human CD300a binds to phosphatidylethanolamine and phosphatidylserine, and modulates the phagocytosis of dead cells. , 2012, Blood.

[34]  S. Erzurum,et al.  Pro-angiogenic hematopoietic progenitor cells and endothelial colony-forming cells in pathological angiogenesis of bronchial and pulmonary circulation , 2011, Angiogenesis.

[35]  J. Stafford,et al.  Increased exposure of phosphatidylethanolamine on the surface of tumor vascular endothelium. , 2011, Neoplasia.

[36]  R. Epand,et al.  Phosphatidylethanolamines Modified by γ-Ketoaldehyde (γKA) Induce Endoplasmic Reticulum Stress and Endothelial Activation* , 2011, The Journal of Biological Chemistry.

[37]  F. Hu,et al.  Lipid and inflammatory biomarkers and kidney function decline in type 2 diabetes , 2010, Diabetologia.

[38]  I. Fidler,et al.  Circulating monocytes expressing CD31: implications for acute and chronic angiogenesis. , 2009, The American journal of pathology.

[39]  M. Koschinsky,et al.  Apolipoprotein(a), through Its Strong Lysine-binding Site in KIV10, Mediates Increased Endothelial Cell Contraction and Permeability via a Rho/Rho Kinase/MYPT1-dependent Pathway* , 2008, Journal of Biological Chemistry.

[40]  J. Witztum,et al.  The role of oxidized phospholipids in mediating lipoprotein(a) atherogenicity , 2008, Current opinion in lipidology.

[41]  H. Cai,et al.  Native, oxidized lipoprotein(a) and lipoprotein(a) immune complex in patients with active and inactive rheumatoid arthritis: plasma concentrations and relationship to inflammation. , 2008, Clinica chimica acta; international journal of clinical chemistry.

[42]  C. Nilsson,et al.  Optimal Blood Mononuclear Cell Isolation Procedures for Gamma Interferon Enzyme-Linked Immunospot Testing of Healthy Swedish and Tanzanian Subjects , 2008, Clinical and Vaccine Immunology.

[43]  J. Prchal,et al.  Redefining endothelial progenitor cells via clonal analysis and hematopoietic stem/progenitor cell principals. , 2007, Blood.

[44]  G. Seydaoglu,et al.  Lipoprotein (A) levels in type 2 diabetic patients with diabetic retinopathy. , 2004, The Medical journal of Malaysia.

[45]  B. Strauss,et al.  Percutaneous Coronary Intervention Results in Acute Increases in Oxidized Phospholipids and Lipoprotein(a): Short-Term and Long-Term Immunologic Responses to Oxidized Low-Density Lipoprotein , 2004, Circulation.

[46]  G. Schmitz,et al.  Lipoprotein (a) downregulates lysosomal acid lipase and induces interleukin-6 in human blood monocytes. , 2003, Biochimica et biophysica acta.

[47]  P. Koolwijk,et al.  Impact of Apolipoprotein(a) on In Vitro Angiogenesis , 2001, Arteriosclerosis, thrombosis, and vascular biology.

[48]  K. Lackner,et al.  Lipoprotein (a) up-regulates the expression of the plasminogen activator inhibitor 2 in human blood monocytes. , 2001, Blood.

[49]  G. Lippi,et al.  Lipoprotein(a): from ancestral benefit to modern pathogen? , 2000, QJM : monthly journal of the Association of Physicians.

[50]  Chulhyun Kim,et al.  High Serum Lipoprotein(a) Levels in Korean Type 2 Diabetic Patients With Proliferative Diabetic Retinopathy , 1998, Diabetes Care.

[51]  R. Klein,et al.  Lp(a) is not Related to Retinopathy in Diabetic Subjects , 1995, European journal of ophthalmology.

[52]  H. Hammes.  Diabetic retinopathy: hyperglycaemia, oxidative stress and beyond , 2017, Diabetologia.