Abstract 5939: Inhomogenous Regulation Of Matrix Metalloproteinases And Their Endogenous Inhibitors Intensifies Cardiac Fibrosis In Zucker Diabetic Fatty Rats

AIM: Experimental and clinical studies have demonstrated that matrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs) are upregulated in dilated failing hearts and involved in the development and progression of myocardial remodelling. However, changes in MMP and TIMP protein levels or activity in the diabetic heart has not yet been described. METHODS: Untreated male Zucker diabetic fatty (ZDF) and Zucker lean (ZL) rats were sacrificed at the age of 6 (prediabetic), 22 (diabetic) and 42 (late diabetes) weeks (wks) and body weight, total heart weight and plasma glucose were measured (n=7, each group). MMP-2, MMP-9 and TIMP-1 were quantified by Western blot analysis of total protein isolated from left ventricular tissue. Expression of MMP/TIMP mRNA was determined by quantitative PCR (Taqman ® ). Additionally paraffin sections of the left ventricular myocardium were stained with Sirius Red to quantify cardiac fibrosis in percent of visual field. RESULTS: (see table1 ) In summary, expression of myocardial MMP-2 and MMP-9 increased, whereas TIMP-1 decreased throughout life in diabetic and non-diabetic animals. However, expression of MMP-2 and MMP-9 was significantly diminished in ZDF compared to ZL rats during various stages of diabetes. TIMP-1 expression was lower in diabetic animals only in the prediabetic stage. Similar results were found in quantitative RT-PCR. The relative amount of fibrosis in left ventricular myocardium was markedly enhanced in late stage of diabetes (ZDF 41% fibrosis/visual field vs. ZL 18%). CONCLUSION: The observed results may play a distinctive role in the remodelling processes in late stages of disease. The regulation of expression of MMPs may, therefore, be a useful therapeutic strategy to manage diabetic cardiomyopathy. Table 1 )