Production of Reactive Oxygen Species in the Diabetic Heart

Abstract

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 ...

Arachidonate 12/15-Lipoxygenase–Induced Inflammation and Oxidative Stress Are Involved in the Development of Diabetic Cardiomyopathy

“…Accumulating evidence suggests that mitochondria and NADPH oxidase important sources of ROS production in the diabetic heart (34)(35)(36), where the crosstalk between mitochondria and NADPH oxidase is important and represents a feed-forward vicious cycle of ROS production (37,38). It is important to elucidate the cellular mechanisms of ROS increase in the diabetic heart.…”

Pathogenesis of Chronic Hyperglycemia: From Reductive Stress to Oxidative Stress

“…Accumulation of glyceraldehyde 3-phosphate can increase the synthesis of diacylglycerol that is an activator of protein kinase C (PKC). PKC activation is known to be involved in elevating the content of TGF- β -1, endothelin-1, NF- κ B, and vascular endothelial growth factor [22, 143, 144] and is also known to induce ROS production by NADPH oxidase that catalyzes one electron reduction of molecular oxygen to form superoxide [145–147]. Mechanistically, it has been established that PKC activates NADPH oxidase by phosphorylating the p47 phox subunit, triggering the translocation of this subunit from cytosol to membrane whereby it assembles with other components to form an active NADPH oxidase that is capable of making superoxide from oxygen [148, 149].…”

Houttuynia cordata aqueous extract attenuated glycative and oxidative stress in heart and kidney of diabetic mice

“…These findings agreed those previous studies and indicated that these two organs were vulnerable to diabetes. NADPH oxidase complex plays an important role in diabetes-induced ROS generation [21,22]. We examined the influence of aqueous extract of H. cordata leaves upon the expression of p47 phox and gp91 phox , NADPH oxidase cytosolic and membrane components, and our data revealed that this extract effectively downregulated cardiac and renal protein expression of p47 phox , which in turn led to lower ROS …”