Abstract
Dysfunction of cardiac mitochondria appears to play a substantial role in cardiomyopathy or myocardial dysfunction and is a promising therapeutic target for many cardiovascular diseases. We investigated the effect of the Rho/Rho-associated protein kinase (ROCK) inhibitor fasudil on cardiac mitochondria from rats in which diabetes was induced by a combination of streptozotocin (STZ) and a sustained high-fat diet. Eight weeks after diabetes was induced by a single intraperitoneal injection of 50 mg/kg STZ followed by a sustained high-fat diet, either fasudil (5 mg/kg bid) or equivalent volumes of saline (control) were administered over four weeks. Fasudil significantly protected against the histopathologic changes of cardiac mitochondria in diabetic rats. Fasudil significantly reduced the abundances of the Rho A, ROCK 1, and ROCK 2 proteins, restored the activities of succinate dehydrogenase (SDH) and monoamine oxidase (MAO) in cardiac mitochondria, inhibited the opening of the mitochondrial permeability transition pore, and decreased the total antioxidant capacity, as well as levels of malonyldialdehyde, hydroxy radical, reduced glutathione, and superoxide dismutase in heart. Fasudil improved the structures of cardiac mitochondria and increased both SDH and MAO activities in cardiac mitochondria. These beneficial effects may be associated with the attenuation of oxidative stress caused by fasudil treatment.
Highlights
Mitochondria are recognized as essential cell organelles, which generate most of the cell’s energy
The final body weights of rats were significantly higher in members of the fasudil-treated and control group compared with members of the diabetes group
Activities of succinate dehydrogenase (SDH) and monoamine oxidase (MAO) were significantly higher in the cardiac mitochondria of fasudil-treated diabetic and control rats compared with those from untreated diabetic rats (Figures 2(a) and 2(b)). These findings suggest that SDH and MAO activity in cardiac mitochondria could be restored by treatment with fasudil
Summary
Mitochondria are recognized as essential cell organelles, which generate most of the cell’s energy. Mitochondria are involved in many physiological activities such as cell signaling, proliferation, growth, and death [1]. They have been implicated in cardiac dysfunction and myocardiocyte damage by the loss of metabolic capacity and the production or release of toxic substances [2]. Diabetes mellitus (DM) is a major cause of serious microvascular and macrovascular diseases, affecting nearly every system in the body. Diabetes-associated metabolic disorders and glycated or oxidized low-density lipoproteins (ox-LDL) impair the activities of enzymes of the mitochondrial respiratory chain complex [6]. Oxidative stress is closely related to mitochondrial dysfunction
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