Activation of CaMKII as a key regulator of reactive oxygen species production in diabetic rat heart

Nishio, S.; Teshima, Yasushi; Takahashi, Naohiko; Thuc, Luong Cong; Saito, Shotaro; Fukui, Atsushi; Kume, Osamu; Fukunaga, Naoya; Hara, Masahide; Nakagawa, Mikiko; Saikawa, Tetsunori

doi:10.1016/j.yjmcc.2012.02.006

Cited by 84 publications

(80 citation statements)

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“…These changes either directly or indirectly result in mitochondrial biogenesis, as measured by increased mitochondrial DNA (mtDNA) and protein complexes. Streptozotocin (STZ) treatment (right side of mitochondrion) leads to increased CaMKII activation by both oxidation (ox) (black circle 2 [15]) and phosphorylation (black circle 3 [16]) with downstream outcomes not shown. Blocking excess mitochondrial ROS generation reduces CaMKII activation, but not AMPK activation (red line 1), and blocking RyR calcium current will reduce CaMKII activation (red line 2).…”

Section: Duality Of Interestmentioning

confidence: 99%

Stress Response Signaling Pathways May Lead to Mitochondrial Biogenesis

Luo

Joiner

2014

Diabetes

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Section: Duality Of Interestmentioning

confidence: 99%

Stress Response Signaling Pathways May Lead to Mitochondrial Biogenesis

Luo

Joiner

2014

Diabetes

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“…Mitochondria were swollen and the structure of the cristae destroyed in the hearts of diabetic rats 4 weeks after STZ injection. 15 Consistently, impairment of mitochondrial respiration and mitochondrial structure have been reported in animal models of type 1 and type 2 DM. 17-20 Mitochondrial respiration and ATP synthesis were decreased in ob/ Figure 1.…”

Section: Uncoupling Proteins As Regulators Of Mitochondrial Ros Produmentioning

confidence: 58%

“…67,68 Therefore, exposure to high glucose concentrations may activate the NHE via PKCdependent mechanisms, 51 and the consequent [Ca 2+ ]i increase will activate CaMKII and NADPH oxidase to generate more ROS (Figure 3). 15 The importance of PKC activation in ROS production in DM was also demonstrated in several reports. The ROS increase induced by high glucose exposure was partially suppressed by a PKC inhibitor.…”

Section: Ages/rage Interactionmentioning

confidence: 70%

“…]i loading increased the phosphorylation of CaMKII and NADPH oxidase expression in cultured cardiomyocytes exposed to high glucose concentrations and also in the hearts of STZ-induced diabetic rats. 15 These results demonstrate the possible contribution of NHE and CaMKII to NADPH oxidase-mediated ROS production in the diabetic heart (Figure 3). Activation of CaMKII may also increase ROS production in mitochondria.…”

mentioning

confidence: 63%

“…Exposure to high glucose concentrations upregulated the expressions of p47phox and p67phox, and increased ROS levels in cultured cardiomyocytes in an apocynin-inhibitable manner. 15 Another group showed that the activity of NADPH oxidase and the expression of Nox4 increased in cardiomyocytes exposed to high glucose. 43 That group also demonstrated that inhibition of Nox4 by antisense oligonucleotides decreased NADPH oxidase activity in the STZ-induced diabetic rat heart.…”

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confidence: 99%

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Production of Reactive Oxygen Species in the Diabetic Heart

Teshima

Takahashi

Nishio

et al. 2014

Circ J

Self Cite

116

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300TESHIMA Y et al. Circulation JournalOfficial Journal of the Japanese Circulation Society http://www. j-circ.or.jp iabetes mellitus (DM) is an independent risk factor of heart failure. The Framingham Heart Study reported that the frequency of heart failure is 2-fold higher in male diabetics and 5-fold higher in female diabetics than in age-matched control subjects. 1 An increase in reactive oxygen species (ROS) has been regarded as a dominant mechanism of cardiac dysfunction in patients with DM. 2-4 ROS are important intracellular signaling molecules and mediate various cellular functions, including activation of transcriptional factors, protein kinases, and ion channels; however, high levels of ROS are detrimental to cardiomyocytes. In physiological conditions, ROS levels are appropriately controlled by endogenous antioxidant systems to minimize oxidative cellular damage. Oxidative stress occurs when ROS production overwhelms antioxidant capacity in pathological conditions. It is apparent that ROS production and oxidative stress are increased in the diabetic heart, and oxidative stress induces various cardiovascular complications, including cardiac dysfunction, which is facilitated by inflammation, apoptosis, and fibrosis (Figure 1). [5][6][7][8] There is accumulating evidence that mitochondria and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase play a pivotal role in ROS production in the diabetic heart. In this review, we will summarize the mechanisms of ROS increase in the diabetic heart focusing on the roles of mitochondria and NADPH oxidase. Mitochondria Mitochondrial ROS Production in DMMitochondria not only provide energy, but also provoke apoptosis, which is regulated by mitochondrial dynamics. 9 Mitochondria also generate ROS as natural byproducts of oxygen metabolism in the electron transport chain. Under normal conditions, most of the electrochemical proton gradient is used to generate ATP through ATP synthase, and only 0.1% of the total oxygen consumption leaks from the respiratory chain to generate ROS. However, a high intracellular glucose concentration increases the flux of electron transfer donors (NADH and FADH2) into the mitochondrial respiratory chain by oxidizing glucose-derived pyruvate. The resulting hyperpolarization of the mitochondrial inner membrane potential partially inhibits electron transport in complex III and accumulates electrons to ubisemiquinone to generate superoxide. 10,11 Therefore, mitochondrial respiration is the principal source of ROS in Reactive oxygen species (ROS) are the main facilitators of cardiovascular complications in diabetes mellitus (DM), and the ROS level is increased in cultured cells exposed to high glucose concentrations or in diabetic animal models. Emerging evidence shows that mitochondria and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase are dominant mechanisms of ROS production in the diabetic heart. Hyperpolarization of the mitochondrial inner membrane potentials and impaired mitochondrial function promote ROS production ...

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Assessment of the protective effect of KN‐93 drug in systemic epilepsy disorders induced by pilocarpine in male rat

Ebrahimi

Sadr

Roghani

et al. 2019

J of Cellular Biochemistry

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Background and Aims Epileptic seizures occur as a consequence of a sudden imbalance between the stimuli and inhibitors within the network of cortical neurons in favor of the stimulus. One of the drugs that induce epilepsy is pilocarpine. Systemic injection of pilocarpine affects on muscarinic receptors. Increasing evidence has addressed the implication of KN‐93 by blocking Ca2+/calmodulin‐dependent protein kinase II (CaMKII), suppressing oxidative stress and inflammation, and also reducing neuron decay. So, we aimed to evaluate the potential preventive effects of KN‐93 in systemic epilepsy disorders induced by pilocarpine. Materials and Methods In this animal study, male rats were divided into five groups including treatment group (KN‐93 with the dose of 5 mM/10 µL dimethyl sulfoxide (DMSO) before inducing epilepsy by 380 mg/kg pilocarpine) KN‐93 group (received 5 mM KN‐93), control group, epilepsy group (received 380 mg/kg pilocarpine Intraperitoneal), and sham group (received 10 µL DMSO). Oxidative stress was assessed by measuring its indicators including the concentration of malondialdehyde (MDA), nitrite, glutathione (GSH), as well as the antioxidant activity of catalase. In addition, serum levels of proinflammatory mediators including tumor necrosis factor‐α (TNF‐α) and interleukin‐1β (IL‐1β) were determined. Results Pretreatment with KN‐93 significantly reduced oxidative stress index by reducing the concentration of MDA, nitrite, and increasing the level of GSH. In addition, low concentrations of TNF‐α and IL‐1β were observed in hippocampus supernatant of KN‐93 pretreated rats in comparison with the pilocarpine groups. Moreover, administration of KN‐93 improved neuronal density and attenuated the seizure activity and behavior. Conclusions Overall, our findings suggest that KN‐93 can effectively suppress oxidative stress and inflammation. Furthermore, KN‐93 is able to attenuate seizure behaviors by preventing its effects on neuron loss, so, it is valuable for the treatment of epileptic seizures.

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Activation of CaMKII as a key regulator of reactive oxygen species production in diabetic rat heart

Cited by 84 publications

References 36 publications

Stress Response Signaling Pathways May Lead to Mitochondrial Biogenesis

Stress Response Signaling Pathways May Lead to Mitochondrial Biogenesis

Production of Reactive Oxygen Species in the Diabetic Heart

Assessment of the protective effect of KN‐93 drug in systemic epilepsy disorders induced by pilocarpine in male rat

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