Pioglitazone Increases Tissue Inhibitors of Metalloproteinase-1 in Plasma in Spontaneously Hypertensive Hyperlipidemic Rats

Abstract

Purpose:: Spontaneously hypertensive hyperlipidemic rats (SHHR) are developed for the early stage model of atherosclerosis (Clin. Exp. Pharmacol. Physiol. 2003). Matrix metalloproteinase-9 (MMP-9) plays an important role in atherosclerosis and retinal degeneration, and is tightly regulated by Tissue inhibitors of metalloproteinases (TIMPs). TIMP-1 especially inhibits MMP-9 and therefore delays the development of retinal degeneration and atherosclerosis. Pioglitazone, Peroxisome Proliferator-Activated Receptor gamma agonists, is reported to decrease MMP-9 activity in vitro, but there are few reports to study effects of Pioglitazone on TIMP-1 activity. We already showed that the increase in plasma and vitreous MMP-9 activities was suppressed by Pioglitazone treatment in high fat diets and 15% sucrose solution (HFDS) treated SHHR (2006 ARVO). In this study, we investigated effects of Pioglitazone on plasma TIMP-1 activity to study whether TIMP-1 is involved in the improvement effects of Pioglitazone on MMP-9 activity.

Methods:: Four months old male SHHR and SD rats were administered N^G-nitro L-arginine methyl ester for one month, then fed HFDS ad libitum for two months, and simultaneously Pioglitazone (3mg/kg or 10mg/kg s.c.) was injected for the same terms. Plasma TIMP-1 in SHHR and SD rats were examined by reverse-gelatine zymography.

Results:: Plasma TIMP-1 activity was significantly increased in HFDS treated SHHR (HFDS-SHHR) and SD rats (HFDS-SD) compared with normal diets treated rats (Control). Plasma TIMP-1 was increased in Pioglitazone treated HFDS-SHHR in a concentration-dependent manner more than non-treated HFDS-SHHR. Whereas, there are little TIMP-1 changes between HFDS-SD and Pioglitazone treated SD rats. Plasma TIMP-1 was significantly increased in Control SD rats and HFDS-SD compared with those in SHHR, respectively.

Conclusions:: TIMP-1 was abundant in HFDS-SD compared with HFDS-SHHR, although MMP-9 activity did not significantly change between both rats. That is one of the reasons for a small vascular change in HFDS-SD compared with HFDS-SHHR. In HFDS-SHHR, Pioglitazone increased plasma TIMP-1 activity. It is suggests that Pioglitazone not only suppresses the increase in MMP-9 activity, but also induces the increase in TIMP-1 activity. Thus Pioglitazone is possible to delay the development of retinal degeneration and vascular changes.

Keywords: drug toxicity/drug effects