Serial Review: Redox-Regulated Phospholipase Signal Transduction
Serial Review Editors: Henry J. Forman, Viswanathan Natarajan
Oxidative stress and redox regulation of phospholipase D in myocardial disease

https://doi.org/10.1016/j.freeradbiomed.2006.03.025Get rights and content

Abstract

Oxidative stress may be viewed as an imbalance between reactive oxygen species (ROS) and oxidant production and the state of glutathione redox buffer and antioxidant defense system. Recently, a new paradigm of redox signaling has emerged whereby ROS and oxidants can function as intracellular signaling molecules, where ROS- and oxidant-induced death signal is converted into a survival signal. It is now known that oxidative stress is involved in cardiac hypertrophy and in the pathogenesis of cardiomyopathies, ischemic heart disease and congestive heart failure. Phospholipase D (PLD) is an important signaling enzyme in mammalian cells, including cardiomyocytes. PLD catalyzes the hydrolysis of phosphatidylcholine to produce phosphatidic acid (PA). Two mammalian PLD isozymes, PLD1 and PLD2 have been identified, characterized and cloned. The importance of PA in heart function is evident from its ability to stimulate cardiac sarcolemmal membrane and sarcoplasmic reticular Ca2+-related transport systems and to increase the intracellular concentration of free Ca2+ in adult cardiomyocytes and augment cardiac contractile activity of the normal heart. In addition, PA is also considered an important signal transducer in cardiac hypertrophy. Accordingly, this review discusses a role for redox signaling mediated via PLD in ischemic preconditioning and examines how oxidative stress affects PLD in normal hearts and during different myocardial diseases. In addition, the review provides a comparative account on the regulation of PLD activities in vascular smooth muscle cells under conditions of oxidative stress.

Introduction

The reactive oxygen species (ROS), such as superoxide anion (O2radical dot), hydrogen peroxide (H2O2), and hydroxyl anion (radical dotOH) as well as other oxidants, such as peroxynitrite (ONOO) and hypochlorous acid (HOCl), are thought to contribute to oxidative stress and cell death [1], [2], [3], [4], [5], [6], [7], [8], [9]. In general, oxidative stress is viewed as an imbalance between oxidant production and antioxidant defense system [10] that affects the redox state of glutathione (GSH). However, recently a new paradigm of redox signaling has emerged whereby some oxidants are considered to function as intracellular signaling molecules. Such signaling can contribute to signaling for either death or survival [11], [12], [13], [14], [15], [16], [17]. It needs to be pointed out that not all the oxidants have a role in signal transduction as this seems to depend upon the cell type and animal species. Furthermore, it is becoming evident that low concentrations of oxidants or exposure for a transient period stimulate the signal transduction mechanisms both for cardiomyocyte function and gene expression for cell survival, while high concentrations of oxidants as well as exposure for a prolonged period produce oxidative stress and subsequent harmful outcomes [10] (Fig. 1). It should also be noted that several factors, including increased levels of hormones, growth factors, and cytokines, can be seen to promote oxidative stress and redox signaling during the development of heart disease [12], [18], [19], [20], [21], [22], [23], [24]. Major sources of ROS are xanthine oxidases, nonphagocytic NADPH oxidases, mitochondria (as a consequence of a leak of electrons to molecular oxygen upstream of cytochrome oxidase), white blood cells and fibroblasts, endothelial cells, autooxidation of catecholamines, and hemoproteins, as well as exposure to radiation or air pollution [10], [25], [26], [27], [28]. In addition, ROS are produced by physical and chemical stressors, such as shear flow [29], [30], [31] or endoplasmic reticulum overload [32], [33].

There is increasing evidence, which suggests that both redox signaling and oxidative stress are involved during the development of cardiac hypertrophy as well as cardiomyopathies, ischemic heart disease, and congestive heart failure (CHF) [10], [34], [35], [36], [37], [38], [39], [40], [41], [42]. Redox signaling is concerned with stimulating the reactions for cellular adaptation and cardioprotection mechanisms, whereas the oxidative stress plays a critical role as a pathogenetic factor. The initial effects of oxidants are, in part, due to the ability of these metabolites to produce modifications in subcellular organelles such as sarcolemma (SL), sarcoplasmic reticulum (SR), mitochondria, and nucleus, which are intimately involved in the regulation of cardiomyocyte Ca2+ homeostasis [10], [43], [44], [45], [46]. On the other hand, the delayed actions of oxidative stress on these subcellular organelles cause an intracellular Ca2+ overload, various deleterious metabolic effects, and subsequent cardiac dysfunction [10], [43], [44], [45], [46]. Accordingly, this review is focused on a discussion of the role of redox signaling in ischemic preconditioning (IP), which is known to produce cardioprotection and to highlight the involvement of phospholipase D (PLD), a key enzyme known to influence cardiac function in normal hearts. In addition, we have attempted to emphasize the involvement of oxidative stress in affecting PLD during the progression of some myocardial diseases, as well as in vascular abnormalities.

Section snippets

Regulation of phospholipase D activities

PLD is recognized as an important component of the signal transduction mechanisms in a variety of cells, including cardiomyocytes. Two mammalian PLD isozymes, PLD1 and PLD2, have been cloned [47]. While PLD1 is localized to the Golgi apparatus and nuclei [48], PLD2 is now recognized as the major myocardial PLD isozyme present in the SL membrane [49]; however, other subcellular localizations of PLD2 have been reported [50], [51]. The hydrolysis of phosphatidylcholine (PC) by PLD is known to

Alterations in phospholipase D by oxidants

Studies in HL-60 granulocytes demonstrated that oxidizing thiol agents activate PLD when this enzyme gets phosphorylated by a tyrosine kinase but not by a PKC [75]. Oxidant-induced activation of PLD in bovine pulmonary artery endothelial cells was also found to be independent of PKC and Ca2+ [76]. In addition, N-ethylmaleimide and phenylarsine oxide, which are known to oxidize free thiols as well as protein thiols, induced phosphatidylethanolamine generation, suggesting PLD activation in

Changes in phospholipase D activities during cardiac ischemia-reperfusion

A decrease in the blood supply to the heart due to atherosclerosis, thrombosis, or coronary artery spasm is known to induce myocardial ischemia. Although reperfusion of the ischemic myocardium during early stages is essential in preventing cardiac damage, reperfusion of the ischemic heart, after a certain critical period, exerts deleterious effects. These abnormalities are represented by contractile dysfunction, an increase in infarct size, ultrastructural damage, and changes in myocardial

Impairment of phospholipase D activities during diabetes

Many of the biochemical pathways, by which diabetes and associated hyperglycemia may cause cellular damage, have been studied. These include the polyol pathway and associated changes in intracellular redox state, increased DAG synthesis with consequent activation of specific PKC isoforms, increased nonenzymatic glycation of intra- and extracellular proteins, altered signal transduction pathways, and oxidative stress. In fact, oxidative stress has been implicated as a major factor in the

Phospholipase D activities during cardiac hypertrophy and heart failure

Heart failure is a major health problem, causing significant morbidity and mortality; however, the pathophysiological signaling events have not been fully elucidated. There is growing evidence that oxidative stress is implicated in the cardiac dysfunction leading to CHF [10], [90], [92], [150], [151], [152], [153], [154]. Experimental and clinical studies have suggested that oxidative stress is enhanced in CHF. For example, it is suggested that there is a possible causal role for increased ROS

Vascular abnormalities due to activation of phospholipase D

Different vascular cells, such as endothelial cells, smooth muscle cells, and fibroblasts, have been shown to generate ROS [168], [169], [170], [171]. Several enzymatic systems including NAD(P)H oxidase, xanthine oxidase, and nitric oxide (NO) synthase, which are capable of producing ROS, have been extensively studied in vascular cells. These enzymes are considered to serve as signaling molecules for the regulation of VSMC function and structure [172], [173], [174], [175]. An increase in the

Concluding remarks

The evidence presented in this review indicates that PLD activities in cardiomyocytes and the vascular cells are regulated by oxidants under pathophysiological conditions. The review also provides an explanation on the paradoxical role of oxidants in the heart. It appears that at low concentrations of oxidants or upon exposure for a transient period, the heart attempts to adapt itself to protect from the harmful effects of these molecules. Such an initial action becomes evident upon stimulation

Acknowledgments

The work reported in this review was supported by grants from the Canadian Institutes of Health Research, Heart and Stroke Foundation of Manitoba, Manitoba Health Reseacrh Council and the St. Boniface Hospital Research Foundation.

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      ROS are endogenously produced largely in the mitochondria by electrons leaking from the respiratory chain during oxidative phosphorylation (Schild and Reiser, 2005). At physiological levels, ROS play several roles including acting as signaling molecules to regulate gene expression (Sauer and Wartenberg, 2005; Tappia et al., 2006), activating redox-sensitive transcription factors (Sen and Packer, 2000) and recruiting platelets and leukocytes during inflammation (West et al., 2011). ROS can be neutralized by antioxidant enzymes such as superoxide dismutase (SOD), glutathione peroxidase (GPOX) and catalase (CAT) and the non-enzymatic vitamins and amino acids (Dröge, 2002).

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    This article is part of a series of reviews on ‘‘Redox-Regulated Phospholipase Signal Transduction.’’ The full list of papers may be found on the home page of the journal.

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