Local non-esterified fatty acids correlate with inflammation in atheroma plaques of patients with type 2 diabetes.
OBJECTIVE
Atherosclerosis is prevalent in diabetic patients, but there is little information on the localization of nonesterified fatty acids (NEFAs) within the plaque and their relationship with inflammation. We sought to characterize the NEFA composition and location in human diabetic atheroma plaques by metabolomic analysis and imaging and to address their relationship with inflammation activity.


METHODS
Time-of-flight secondary ion mass spectrometry (TOF-SIMS) was used for metabolomic analysis imaging of frozen carotid atheroma plaques. Carotid endarterectomy specimens were used for conventional immunohistochemistry, laser-capture microdissection quantitative PCR, and in situ Southwestern hybridization. Biological actions of linoleic acid were studied in cultured vascular smooth muscle cells (VSMCs).


RESULTS
TOF-SIMS imaging evidenced a significant increase in the quantity of several NEFA in diabetic versus nondiabetic atheroma plaques. Higher levels of NEFA were also found in diabetic sera. The presence of LPL mRNA in NEFA-rich areas of the atheroma plaque, as well as the lack of correlation between serum and plaque NEFA, suggests a local origin for plaque NEFA. The pattern of distribution of plaque NEFA is similar to that of MCP-1, LPL, and activated NF-kappaB. Diabetic endarterectomy specimens showed higher numbers of infiltrating macrophages and T-lymphocytes-a finding that associated with higher NEFA levels. Finally, linoleic acid activates NF-kappaB and upregulates NF-kappaB-mediated LPL and MCP-1 expression in cultured VSMC.


CONCLUSIONS
There is an increased presence of NEFA in diabetic plaque neointima. NEFA levels are higher in diabetic atheroma plaques than in nondiabetic subjects. We hypothesize that NEFA may be produced locally and contribute to local inflammation.
Mas
Sebastián
S
Vascular Pathology and Experimental Nephrology Laboratory, Fundación Jiménez Díaz/Autonoma University/IRSIN, Madrid, Spain. smas@fjd.es
Martínez-Pinna
Roxana
R
Martín-Ventura
Jose Luis
JL
Pérez
Raul
R
Gomez-Garre
Dulcenombre
D
Ortiz
Alberto
A
Fernandez-Cruz
Arturo
A
Vivanco
Fernando
F
Egido
Jesús
J
D000368:Aged; D050197:Atherosclerosis / Q000097:blood* / Q000276:immunology / Q000473:pathology*; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure; D016893:Carotid Stenosis / Q000601:surgery; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000150:complications / Q000473:pathology*; D003925:Diabetic Angiopathies / Q000097:blood* / Q000473:pathology / Q000601:surgery; D016894:Endarterectomy, Carotid; D005230:Fatty Acids, Nonesterified / Q000097:blood*; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood; D006973:Hypertension / Q000097:blood; D007249:Inflammation / Q000097:blood*; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology
D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D012313:RNA