TNF-α-induced mitochondrial oxidative stress and cardiac dysfunction: restoration by superoxide dismutase mimetic Tempol

Abstract

Mitochondria are indispensable for bioenergetics and for the regulation of physiological/signaling events in cellular life. Although TNF-alpha-induced oxidative stress and mitochondrial dysfunction are evident in several pathophysiological states, the molecular mechanisms coupled with impaired cardiac function and its potential reversal by drugs such as Tempol or apocyanin have not yet been explored. Here, we hypothesize that TNF-alpha-induced oxidative stress compromises cardiac function by altering the mitochondrial redox state and the membrane permeability transition pore (MPTP) opening, thereby causing mitochondrial dysfunction. We measured the redox states in the cytosol and mitochondria of the heart to understand the mechanisms related to the MPTP and the antioxidant defense system. Our studies demonstrate that TNF-alpha-induced oxidative stress alters redox homeostasis by impairing the MPTP proteins adenine nucleotide translocator and voltage-dependent anion channel, thereby resulting in the pore opening, causing uncontrolled transport of substances to alter mitochondrial pH, and subsequently leading to dysfunction of mitochondria and attenuated cardiac function. Interestingly, we show that the supplementation of Tempol along with TNF-alpha restores mitochondrial and cardiac function.

Effects of caffeic acid on doxorubicin induced cardiotoxicity in rats

“…Although the precise biochemical mechanisms of Dox cardiotoxicity remain uncertain, it has been demonstrated that the cardiac toxicity associated with Dox administration is mediated, at least in part, by induction of oxidative stress [41] and cardiac cell apoptosis [42]. Redox signals play vital roles in the pathogenesis of acute and chronic stress conditions by mediating the expression patterns of proteins and genes associated with redox balance [43].…”

Increased propensity for cell death in diabetic human heart is mediated by mitochondrial-dependent pathways

“…Mechanisms by which these metabolic stressors cause alterations in the biochemistry of cardiac mitochondria remain a focus of intense research and are likely a collective result of a multifaceted degenerative process comprised of oxidative mitochondrial DNA damage (20), posttranslational modification of mitochondrial enzymes (10, 13), alterations in mitochondrial membrane architecture (55), and compromised antioxidant defenses (23,27). Inflammatory cytokines such as tumor necrosis factor (TNF)-␣, known to be elevated in patients with metabolic syndrome and type 2 diabetes, have also been shown to stimulate mitochondrial ROS (39,53) and cardiomyocyte death (32,42) in part through activation of a sphingolipid/ceramide-mediated lipotoxic pathway (53). However, the increased mitochondrial ROS and mPTP sensitivity to Ca 2ϩ seen in diabetic heart tissue in the present study is unlikely to be driven by a ceramide-mediated pathway, since recent findings by Baranowski et al (8) showed that ceramide levels are not increased in atrial appendage from obese, type 2 diabetic patients compared with obese, nondiabetic patients.…”

The role of oxidative stress in renal injury induced in rats by losartan exposure during lactation

“…The combination of losartan with tempol was based on a study by Dobrian et al 27 Tempol is a small molecule that is able to cross biological membranes, and the treatment of rats with this compound was able to decrease both cytosolic and mitochondrial ROS production. 28 At 21 and 60 days old, the pups were anesthetized, blood and urine samples were collected to analyze renal function, and the kidneys were perfused via the left cardiac ventricle (21 days) or aorta (60 days) with phosphate-buffered solution (PBS; 0.15 M NaCl and 0.01 M sodium phosphate buffer, pH 7.4). One kidney was removed for Western blotting, lipid peroxidation and glutathione quantification.…”