Ruboxistaurin attenuates hypertriglyceridemia in diabetic rats: comparison with the antioxidant N-acetylcysteine

Abstract

Hyperglycemia-induced oxidative stress plays a critical role in the development of diabetic metabolic complications including hypertriglyceridemia. The beta isoform of Protein kinase C (PKCβ) is over-expressed in various organs of diabetic rodents and can cause or exacerbate oxidative stress by activating NADPH oxidase, a major source of superoxide production in the cardiovascular system. We postulated that selective PKCβ inhibition with ruboxistaurin (RXT) may attenuate hypertriglyceridemia in diabetes by reducing oxidative stress. Control or streptozotozin-induced diabetic rats were either untreated (C, D) or treated with RXT (1 mg/kg/day, D+RXT) or with the antioxidant N-acetylcycsteine (NAC) (1.5g/kg/day, D+NAC) delivered by oral gavage for four weeks. Levels of 15-F2t-isoprostane (IsoP), a specific marker of oxidative stress, were significantly increased in D group in both the myocardium and plasma. This was accompanied by a marked increase in plasma triglycerides (P<0.05 vs. C). RXT and NAC, respectively, prevented the increase of IsoP and significantly attenuated the increases of triglycerides. However, triglycerides in the D+NAC group was lowered further than that in the D+RXT group (P<0.05). Despite similar antioxidant properties, ruboxistaurin seems to be inferior to NAC in reducing hypertriglyceridemia in diabetes.