⌘+K

September 10, 2026Journal of Molecular HistologyOpen Access

High TG/low HDL-C ratio–mimetic lipid stress drives diabetic atherosclerotic endothelial–macrophage dysfunction through glycocalyx disruption and CD36/ABCA1 imbalance

View Full Paper

Ask AI

Bookmark

Share

Key result

High TG/low HDL-C stress cuts endothelial barrier integrity ~57%, attenuated by HDL rescue.

n=6

Why the study?

The cellular mechanisms linking a high TG/low HDL-C ratio to vascular injury in insulin resistance and atherosclerotic cardiovascular risk remain incompletely defined.

Does combined hyperglycemic and high TG/low HDL-C ratio-mimetic lipid stress induce endothelial glycocalyx disruption and macrophage foam-cell formation in vitro, and can HDL or ApoA-I rescue attenuate these effects?

Key Points

To delineate the cellular mechanisms by which a high triglyceride/low HDL-C ratio drives endothelial injury, glycocalyx breakdown, and macrophage foam-cell formation in diabetic atherosclerosis.
Cultured human coronary artery endothelial cells and THP-1 macrophages under combined high glucose (25 mM), high VLDL (300 mg/dL TG equivalent), and low HDL (25 mg/dL HDL-C equivalent) conditions.
Evaluated endothelial barrier function, glycocalyx shedding, inflammatory markers, and macrophage cholesterol efflux following rescue with HDL (100 mg/dL HDL-C equivalent), ApoA-I (50 µg/mL), or specific pathway inhibitors.
Combined stress decreased endothelial cell viability by 17.3%, increased LDH release by 111.4%, and reduced transendothelial electrical resistance by 57% from approximately 44 to 19 Ω·cm².
FITC-dextran permeability and syndecan-1 shedding each increased to approximately 3.2-fold of control, accompanied by a 3.8-fold rise in HPSE expression and a 40–55% decrease in SDC1, TJP1, and CDH5.
Endothelial lipid stress upregulated macrophage CD36 and suppressed ABCA1-associated cholesterol efflux, whereas HDL rescue attenuated barrier disruption and CD36 inhibition reduced macrophage lipid accumulation.

Structured PICO

Does combined hyperglycemic and high TG/low HDL-C ratio-mimetic lipid stress induce endothelial glycocalyx disruption and macrophage foam-cell formation in vitro, and can HDL or ApoA-I rescue attenuate these effects?

P

Population

In vitro cellular model using primary human coronary artery endothelial cells (HCAECs) and THP-1-derived macrophages across 6 independent biological replicates exposed to hyperglycemic and high TG/low HDL-C lipid stress for 24 to 48 hours.

I

Intervention

Combined hyperglycemic and high TG/low HDL-C ratio-mimetic medium (25 mM D-glucose, VLDL adjusted to 300 mg/dL triglyceride equivalent, and HDL adjusted to 25 mg/dL HDL-C equivalent) for 24 hours (HCAECs) or 48 hours (macrophages in HCAEC-conditioned medium), evaluated alongside rescue interventions with intact HDL (100 mg/dL HDL-C equivalent), purified ApoA-I (50 µg/mL), CD36 inhibitor sulfo-N-succinimidyl oleate (SSO, 100 µM), or heparanase inhibitor OGT2115 (1 µM).

C

Comparator

Physiological-range lipid control medium (5.5 mM glucose, VLDL adjusted to 100 mg/dL triglyceride equivalent, and HDL adjusted to 60 mg/dL HDL-C equivalent), D-mannitol osmotic control, isolated high-glucose medium (25 mM D-glucose), and isolated TG-rich lipoprotein medium (VLDL 300 mg/dL TG equivalent).

O

Outcome

Endothelial barrier and glycocalyx integrity (transendothelial electrical resistance [TEER], FITC-dextran permeability, syndecan-1 shedding, WGA staining, ZO-1, VE-cadherin) at 24 hours, monocyte adhesion and transmigration, and macrophage foam-cell formation (Oil Red O-positive area, total cholesterol, cholesteryl ester) and cholesterol efflux at 48 hours.surrogate

Main Result

Absolute Event Rate: 45.8% vs 8.5%

Limitations

In vitro cell culture study using HCAECs and THP-1-derived macrophages rather than in vivo models
Supportive datasets were based on three independent biological replicates
CD36 protein abundance was not assessed in the CD36 inhibitor (SSO) experiment
In vitro experimental design utilizing cultured HCAECs and THP-1-derived macrophages
Some supportive datasets were based on three independent biological replicates
CD36 protein abundance was not assessed in the CD36 inhibitor experiment

Ask about this paper

Answers are grounded in this paper and cite their sources.

Implication

Identifies the endothelial glycocalyx-NF-κB-CD36/ABCA1 axis as a cellular mechanism linking a high TG/low HDL-C ratio and hyperglycemia to endothelial barrier injury and macrophage foam-cell formation.

Abstract

A high triglyceride/high-density lipoprotein cholesterol (TG/HDL-C) ratio is strongly associated with insulin resistance and atherosclerotic cardiovascular risk, but the cellular mechanisms linking this lipid imbalance to vascular injury remain incompletely defined. This study established a combined hyperglycemic/high TG/low HDL-C ratio-mimetic in vitro model using human coronary artery endothelial cells and THP-1-derived macrophages to investigate endothelial inflammation, glycocalyx disruption, monocyte recruitment, foam-cell formation, oxidative stress, and cholesterol efflux. High TG/low HDL-C ratio-mimetic stress significantly reduced endothelial viability, increased cytotoxicity, impaired transendothelial resistance, increased fluorescein isothiocyanate (FITC)-dextran permeability, and promoted syndecan-1 shedding. The lipid-stress condition induced endothelial inflammatory activation, with increased vascular cell adhesion molecule 1 (VCAM1), intercellular adhesion molecule 1 (ICAM1), E-selectin (SELE), C-C motif chemokine ligand 2 (CCL2), interleukin 6 (IL6), and C-X-C motif chemokine ligand 8 (CXCL8) expression, accompanied by enhanced THP-1 adhesion and transmigration. Glycocalyx and junctional injury were supported by increased heparanase (HPSE) expression and reduced syndecan-1 (SDC1), tight junction protein 1 (TJP1), cadherin 5 (CDH5), wheat germ agglutinin (WGA) staining, zonula occludens-1 (ZO-1) continuity, and vascular endothelial cadherin (VE-cadherin) integrity. Endothelial-conditioned lipid stress promoted macrophage foam-cell formation, increased CD36 scavenger receptor (CD36), oxidized low-density lipoprotein receptor 1 (OLR1), and peroxisome proliferator-activated receptor gamma (PPARG) expression, enhanced cholesterol accumulation, and suppressed ATP-binding cassette transporter A1 (ABCA1)-, ATP-binding cassette transporter G1 (ABCG1)-, scavenger receptor class B member 1 (SCARB1)-, and apolipoprotein E (APOE)-associated cholesterol efflux pathways. HDL rescue broadly attenuated endothelial inflammation, oxidative stress, barrier disruption, and macrophage foam-cell formation, whereas ApoA-I exerted protective effects across the selected endothelial and macrophage endpoints in which it was evaluated. CD36 inhibition reduced macrophage lipid accumulation, whereas heparanase inhibition preserved glycocalyx integrity. These findings identify the endothelial glycocalyx-nuclear factor kappa B (NF-κB)-CD36/ABCA1 axis as a mechanistic link between the high TG/low HDL-C ratio and diabetic atherosclerotic vascular dysfunction.

Discussion

No takes yet. Share an insight, caveat, or question.

Cite This Study

Bi et al. (2026) studied Diabetic atherosclerotic endothelial and macrophage dysfunction (in vitro cell culture model) (n=6). Combined hyperglycemic/high TG/low HDL-C ratio-mimetic lipid stress, plus HDL rescue, ApoA-I rescue, CD36 inhibition (SSO), or heparanase inhibition (OGT2115) vs. Physiological-range lipid control medium (5.5 mM glucose, VLDL 100 mg/dL TG equivalent, HDL 60 mg/dL HDL-C equivalent) and mannitol osmotic control was evaluated on Endothelial barrier integrity (transendothelial electrical resistance [TEER]) and macrophage foam-cell formation (Oil Red O-positive area).

synapsesocial.com/papers/6aa51ebf327956e4761f8894 https://doi.org/10.1007/s10735-026-10971-4

View Full Paper

Ask AI

Bookmark

Share