Changes in superoxide dismutase mRNA expression by streptozotocin‐induced diabetes

Abstract

Experiments were designed to investigate the involvement of superoxide anions in the attenuated endothelium‐dependent relaxation of the rat aorta from streptozotocin (STZ)‐induced diabetic rats. The endothelium‐dependent relaxation responses to acetylcholine (ACh, 10−7 m) in helical strips of the aorta precontracted with noradrenaline (NA, 5 × 10−8∼3 × 10−7 m) were significantly decreased in STZ‐induced diabetic rats. The recovery phase of the relaxation after single administration of ACh in the STZ‐induced diabetic rats was more rapid than those in control vessels. Preincubation of aortic strips with superoxide dismutase (SOD, 60 u ml−1) normalized the recovery phase of the relaxation of diabetic aorta after single administration of ACh, whereas catalase (150 u ml−1) or indomethacin (10−5 m) had no effects on the relaxation. SOD (180 u ml−1) caused relaxation in NA precontracted aortic strips and the degree of the SOD‐induced relaxation was significantly greater in diabetic aorta as compared with age‐matched control vessels. When the changes in mRNA expressions of Mn‐SOD or Cu‐Zn‐SOD were observed, Mn‐SOD mRNA expression was markedly decreased, and Cu‐Zn‐SOD was slightly decreased in diabetic aorta. These results suggest that the rapid destruction of NO by superoxide anions may occur in the STZ‐induced diabetic rats, and this may be due to a decrease in mRNA expression of Mn‐SOD or Cu‐Zn‐SOD.

Effects of chronic administration of the novel endothelin antagonist J‐104132 on endothelial dysfunction in streptozotocin‐induced diabetic rat

“…Our success in this regard is evidenced in the present study by the ®nding that a relaxation of over 80% of the noradrenaline-induced contraction was induced by as little as 10 77 M ACh ( Figure 1a). The reduced endothelium-dependent relaxation seen in diabetic rats in the present study is in agreement with the results of numerous other studies on aortae from STZinduced diabetic rats (Oyama et al, 1986;Kamata et al, 1989;Poston & Taylor, 1995;Pieper, 1998;Kamata & Kobayashi, 1996;Kobayashi & Kamata, 1999a, b;Kobayashi et al, 2000;De Vriese et al, 2000;Hink et al, 2001).…”

“…A considerable body of evidence now suggests that the impairment of endothelium-dependent relaxation seen in diabetes and atherosclerosis may involve inactivation of NO by oxygen-derived free radicals (Kamata & Kobayashi, 1996;Kobayashi & Kamata, 1999a;Meraji et al, 1987;Pieper et al, 1992;Hattori et al, 1991;Ooboshi et al, 1997;Lund et al, 1999;Pagano et al, 1998). Production of superoxide anion inactivates NO (Marshall et al, 1988;Rubanyi & Vanhoutte, 1986;Kobayashi & Kamata, 2001) and dismutation of free radicals has generally (Pieper et al, 1996;Hattori et al, 1991;Kamata & Kobayashi, 1996) but not always (Heygate et al, 1995) been found to improve impaired endothelium-dependent relaxation in experimental models of diabetes.…”

“…Production of superoxide anion inactivates NO (Marshall et al, 1988;Rubanyi & Vanhoutte, 1986;Kobayashi & Kamata, 2001) and dismutation of free radicals has generally (Pieper et al, 1996;Hattori et al, 1991;Kamata & Kobayashi, 1996) but not always (Heygate et al, 1995) been found to improve impaired endothelium-dependent relaxation in experimental models of diabetes. Indeed, we recently reported that NO is metabolized by O 2 7 to NO 3…”

“…We have also reported that the overproduction of ET-1 seen in STZ-induced diabetes is a result of hyperglycaemia, not of an increase in LDL cholesterol or triglyceride (Makino & Kamata, 2000). Taken together, the above evidence suggests that the ®nding that J-104132 induces an improvement in the endothelial dysfunction seen in STZ-induced diabetic rats may be explained by the following sequence of events: (i) the plasma ET-1 concentration is increased in STZ-induced diabetic rats; (ii) the increased ET-1 may stimulate NADPH oxidase, which produces O 2 7 ; (iii) the additional O 2 7 may not be metabolized to H 2 O 2 because superoxide dismutase activity is decreased in STZ-induced diabetic rats (Kamata & Kobayashi, 1996;Kobayashi & Kamata, 1999b), a disorder that may lead to an abnormal NO metabolism and a subsequent impairment of endothelium-dependent relaxation; (iv) when J-104132 is chronically administered to STZinduced diabetic rats, it may have a long-term antagonistic e ect on the ET-1-induced stimulation of NADPH oxidase. As a consequence, the enhanced O 2 7 level seen in these animals would be normalized, as indeed we found in the present study, thereby resulting in an improvement in the endothelial dysfunction.…”

The PI3-K/Akt pathway: roles related to alterations in vasomotor responses in diabetic models

“…It has been suggested that the excessive elevations in plasma glucose, insulin, low density lipoprotein (LDL) cholesterol, endothelin-1 (ET-1), Ang II, and reactive oxygen species that occur in diabetes are involved in the development of this dysfunction in several blood vessels. Indeed, a considerable body of evidence now suggests that in type I diabetes, the observed impairment of endothelial function may involve inactivation of NO by oxygen-derived free radicals (Meraji et al, 1987;Hattori et al, 1991;Pieper et al, 1992;Tesfamariam, 1994;Keaney and Vita, 1995;Kamata et al, 1996a;Ooboshi et al, 1997;Kobayashi and Kamata, 1999a, 2002b. In experimental models of type I diabetes, an enhancement of NO production (which in such models is diminished by superoxide anion) and dismutation of free radicals has generally been found to improve impaired endothelium-dependent relaxation (Rubanyi and Vanhoutte, 1986;Marshall et al, 1988;Kobayashi and Kamata, 2001).…”