Effect of new thiazolidine derivatives LPSF/GQ-02 and LPSF/GQ-16 on atherosclerotic lesions in LDL receptor-deficient mice (LDLR(-/-)).
BACKGROUND
Atherosclerotic cardiovascular disease is a chronic inflammatory condition. Thiazolidinediones (TZDs) are used to enhance sensitivity to insulin and have demonstrated a protective effect over a variety of cardiovascular markers and risk factors. Controversially, the TZDs are associated with the development of heart failure. Thus, lines of research have invested in the search for new molecules in order to obtain more selective and less harmful treatment alternatives for the pathogenesis of atherosclerosis and its risk factors.


METHODS
Animals were fed a diet rich in fat for 10 weeks. In the last 2 weeks, animals received either pioglitazone, LPSF/GQ-02, or LPSF/GQ-16 daily through gavage. At the end of the treatment, blood was collected for biochemical analysis and the aortas were dissected for subsequent analyses.


RESULTS
No changes in the blood lipid profile were found following the use of the drugs in comparison to the control. However, the new thiazolidine derivatives were more efficient in improving insulin resistance in comparison to pioglitazone and the control group. Morphometric analyses revealed that neither pioglitazone nor LPSF/GQ16 led to satisfactory effects over atherosclerosis. However, LPSF/GQ-02 led to a reduction in area of the atherosclerotic lesions. Ultrastructural analyses revealed extensive degeneration of the endothelium and an increase in apoptotic cells in the subendothelial space following the use of pioglitazone and LPSF/GQ-16. However, LPSF/GQ-02 caused minimal cell alterations in the aortic endothelium. Regarding markers, endothelial nitric oxide synthase (eNOS) and matrix metalloproteinase 9 (MMP-9), LPSF/GQ-16, and pioglitazone exerted similar effects, increasing the expression of MMP-9, and had no effect on the expression of eNOS compared with the control group. On the other hand, LPSF/GQ-02 was effective in reducing the expression of MMP-9 and increased eNOS significantly.


CONCLUSIONS
The results suggest that the new thiazolidine derivative LPSF/GQ-02 is a promising candidate for the treatment of atherosclerosis.
Laboratório de Ultraestrutura, Centro de Pesquisa Aggeu Magalhães, FIOCRUZ, Recife, Brazil. kls.amanda@gmail.com
Amanda Karolina
AK
Soares E Silva
Dilênia
D
de Oliveira Cipriano Torres
Sura Wanessa
SW
Santos Rocha
Fabiana Oliveira
FO
dos Santos Gomes
Bruna
B
dos Santos Silva
Mariana Aragão Matos
MA
Donato
Catarina
C
Raposo
Ana Célia Oliveira
AC
Santos
Maria do Carmo Alves
Mdo C
de Lima
Suely Lins
SL
Galdino
Ivan
I
da Rocha Pitta
José Roberto Botelho
JR
de Souza
Christina Alves
CA
Peixoto
D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D001018:Aortic Diseases / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects; D050197:Atherosclerosis / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D015153:Blotting, Western; D002317:Cardiovascular Agents / Q000494:pharmacology* / Q000633:toxicity; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008055:Lipids / Q000097:blood; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D000077205:Pioglitazone; D058226:Plaque, Atherosclerotic; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000633:toxicity; D053778:Thiazolidines / Q000494:pharmacology* / Q000633:toxicity; D013997:Time Factors
C581247:5-(4-chlorobenzylidene)-3-(4-methylbenzyl)thiazolidine-2,4-dione; C576055:5-(5-bromo-2-methoxybenzylidene)-3-(4-methyl-benzyl)thiazolidine-2,4-dione; D001786:Blood Glucose; D002317:Cardiovascular Agents; D007328:Insulin; D008055:Lipids; D011973:Receptors, LDL; D045162:Thiazolidinediones; D053778:Thiazolidines; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D000077205:Pioglitazone