Beneficial effects of C36, a novel breaker of advanced glycation endproducts cross-links, on the cardiovascular system of diabetic rats.
OBJECTIVE
Advanced glycation endproducts (AGE) have been implicated in the pathogenesis of diabetic complications, including diabetic cardiovascular dysfunctions. 3-benzyloxycarbonylmethyl-4-methyl-thiazol-3-ium bromide (C36), a novel AGE breaker, was investigated for its beneficial effects on the cardiovascular system of diabetic rats.


METHODS
The in vitro breaking abilities of C36 on AGE cross-links formed in vitro and in vivo were assessed. After 4 weeks' treatment with C36, cardiovascular and left ventricular functions in diabetic (streptozotocin-induced) rats were evaluated by haemodynamic studies. Effects of C36 on AGE accumulation, collagen distribution, and fibrosis-associated gene expression were also investigated by biochemical and morphological methods and reverse transcription-PCR, respectively.


RESULTS
In vitro, C36 released bovine serum albumin (BSA) from preformed AGE-BSA-collagen complexes and decreased the IgG cross-linked to red blood cell surface (RBC-IgG). In vivo, C36 treatment of diabetic rats resulted in a significant increase in left ventricular systolic pressure and the maximal rate of left ventricular pressure rise and pressure fall, induction in cardiac output and systemic arterial compliance, decrease of total peripheral resistance, reduction of diabetes-induced RBC-IgG content, increase of myocardial and tail tendon collagen solubility, and normalization of collagen type III/I ratio in diabetic rats. In addition, C36 treatment attenuated mRNA levels of diabetes-induced genes, including receptors for AGE, transforming growth factor beta1, connective tissue growth factor, and collagen III.


CONCLUSIONS
C36 was an effective breaker of AGE cross-links and had beneficial effects on the cardiovascular system of diabetic rats.
Cheng
G
G
Beijing Institute of Pharmacology and Toxicology, Beijing, China.
Wang
L-L
LL
Long
L
L
Liu
H-Y
HY
Cui
H
H
Qu
W-S
WS
Li
S
S
D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D002318:Cardiovascular Diseases / Q000188:drug therapy* / Q000209:etiology; D003094:Collagen / Q000187:drug effects / Q000378:metabolism; D003187:Compliance / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000503:physiopathology*; D004912:Erythrocytes / Q000187:drug effects / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors*; D007074:Immunoglobulin G / Q000187:drug effects / Q000276:immunology; D008297:Male; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012710:Serum Albumin, Bovine / Q000187:drug effects / Q000378:metabolism; D013311:Streptozocin; D013844:Thiazoles / Q000494:pharmacology*; D014655:Vascular Resistance / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects*
C526536:3-benzyloxycarbonylmethyl-4-methylthiazol-3-ium; D017127:Glycation End Products, Advanced; D007074:Immunoglobulin G; D012333:RNA, Messenger; D013844:Thiazoles; D012710:Serum Albumin, Bovine; D013311:Streptozocin; D003094:Collagen