4-THIAPROLINE REDUCES HEART LIPID-PEROXIDATION AND COLLAGEN ACCUMULATION IN THE DIABETIC DB DB MOUSE/

Collagen accumulation is a main pathological feature of diabetic cardi omyopathy. The underlying mechanisms seem to be increased cross linkin g by reactive carbonyles. The purpose of the study was to decrease the collagen content of total ventricular tissue by the oral administrati on of thiaproline, which could reduce collagen due to its functions as a proline analogue, blocking collagen production and as a free oxygen radical scavenger, blocking reactive carbonyles and oxygen species an d subsequently collagen cross linking. Thiaproline was administered to genetically diabetic db/db mice and compared to untreated animals. To tal ventricular collagen as expressed by hydroxyproline was significan tly lower in the treated group (means 0.23 micromoles/100 mg tissue in the treated vs 0.35 micromoles/100 mg tissue in the untreated group, p < 0.001). Significantly more collagen could be eluted in the treated group (p < 0.001) and carboxymethyllysine was significantly reduced i n the treated group (p < 0.001). Di-tyrosine and glycemic control did not differ between the groups. Glutathione was significantly increased in the TP treated experimental group (p < 0.001) and lipid peroxidati on products were significantly decreased (means 0.221 absorbance in th e treated group versus 0.321 absorbance in the untreated diabetic grou p) correlating with total ventricular collagen content (r = 0.87, p < 0.001). We conclude that thiaproline reduced total ventricular collage n content by inhibiting collagen cross linking as reflected by increas ed solubility of collagen and expressed by higher elution quantity of collagen. Thiaproline, and/or its metabolites induced increase of hear t glutathione which may well have been scavenging reactive carbonyles derived from lipid peroxidation and advanced stage nonenzymatic glycos ylation as shown by decreased total ventricular carboxy-methyllysine a nd lipid peroxidation products paralleling reduced heart collagen cont ent. It remains to be shown that the successful reduction of heart col lagen by thiaproline is paralleled by improved functional properties.