Cardiovasc Drugs Ther DOI 10.1007/s10557-015-6571-z


ATM Protein Kinase Signaling, Type 2 Diabetes and Cardiovascular Disease Yolandi Espach & Amanda Lochner & Hans Strijdom & Barbara Huisamen

# Springer Science+Business Media New York 2015

Abstract The ataxia-telangiectasia mutated (ATM) protein kinase is well known to play a significant role in the response to double stranded DNA breaks in the nucleus. Recently, it has become apparent that ATM is also involved in a large number of cytoplasmic processes and responses, some of which may contribute to metabolic and cardiovascular complications when disrupted. Due to its involvement in these processes, therapeutic activation of ATM could potentially be a novel approach for the prevention or treatment of cardiovascular disease. However, relatively little is currently known about the cardiovascular role of ATM. In this review, we highlight studies that have shed some light on the role of ATM in the cardiovascular context, namely in oxidative stress, atherosclerosis and metabolism, insulin resistance and cardiac remodeling. Keywords Cardiovascular disease . Insulin resistance . Ataxia telangiectasia . Oxidative stress . Type 2 diabetes

Introduction Westernized diets high in sugar and fat, accompanied by sedentary lifestyles are leading to a higher incidence of obesity and type 2 diabetes mellitus in the global population. This, in turn, contributes to more people experiencing cardiovascular disease, which is currently the leading cause of death globally Y. Espach (*) : A. Lochner : H. Strijdom : B. Huisamen Division of Medical Physiology, Department of Biomedical Sciences, Faculty of Health Sciences, University of Stellenbosch, Tygerberg, South Africa e-mail: [email protected] B. Huisamen MRC DDP, Parow, South Africa

according to the World Health Organization. Recently, a potential link between defective ATM protein signaling and features of the metabolic syndrome has emerged, such as insulin resistance, hyperglycemia and atherosclerosis, and it is becoming increasingly apparent that defects in activation or expression of ATM could play an as yet unexplored role in the development of cardiomyopathy. The ATM protein is encoded by the ATM gene, which is located on chromosome 11q22-23 [1]. When mutated, the lack of functional ATM protein leads to ataxia-telangiectasia (A-T), an autosomal recessive disease which manifests in early childhood [2]. The disease affects 1 in 40 000 to 1 in 200 000 individuals globally, with an estimated 2.8 % of the global population being A-T carriers [3, 4]. The most prominent characteristics of A-T are cerebellar neurodegeneration, oculocutaneous telangiectasia, immunodeficiency, a high risk for cancer, premature ageing and radiosensitivity [2, 5, 6]. Patients also display growth retardation, insulin resistance and glucose intolerance [6]. Carriers of the disease were found to die approximately 4 years earlier than non-carriers due to the development of cancer and approximately 11 years earlier due to ischemic heart disease [2, 7]. ATM has a molecular mass of 350 kDa and belongs to the phosphatidylinositol 3-kinase like kinase (PIKK) family, which phosphorylates substrates on serine or threonine residues that are followed by glutamine [8]. ATM is present in mammalian cells as dimers or higher-order multimers in which the kinase domains are blocked, rendering the ATM molecules inactive when in the complex. Multiple stressors give rise to the activation of ATM, which, in turn, leads to the phosphorylation of different substrates [9]. There are currently two different mechanisms known for the activation of ATM. Firstly, activation of ATM occurs in response to doublestranded DNA breaks and happens via interaction with the MRE11-RAD50-NBS1 (MRN) complex [10]. Once stimulated, serine 1981 will be autophosphorylated in each ATM

Cardiovasc Drugs Ther

molecule present in the complex by the kinase domain of a neighboring ATM molecule, causing the complex to dissociate into active monomers [5]. Although many studies regard serine 1981 phosphorylation as the principle mechanism of ATM activation, ATM kinase activity has been reported in the absence of serine 1981 autophosphorylation [9, 11]. The phosphatases, Wip1 and PP2A, regulate ATM phosphorylation. The scaffolding and catalytic subunits of PP2A associate with ATM in unstressed cells to prevent autophosphorylation of ATM [12], while Wip1 dephosphorylates ATM after the stressor is removed [13]. The second known mechanism by which ATM is activated, is via oxidation during exposure to oxidative stress. When oxidized, ATM undergoes conformational changes by forming intermolecular disulfide bonds at cysteine 2991, among others [9]. These disulfide bonds are essential for ATM activation due to oxidative stress and cause the activated ATM to remain in covalently bound dimers [9]. Besides being activated by DNA breaks and oxidative stress, ATM is also known to be activated by hypoxia and insulin, however, these mechanisms are yet to be elucidated. More than 490 proteins which form part of various signaling pathways, were identified as substrates of ATM in a large proteomic study [14]. It was initially thought that ATM is present in the nucleus only, where it plays an important role as a sensor of double-stranded DNA breaks. By phosphorylating proteins such as p53, Chk2, BRCA1 and H2AX, nuclear ATM initiates cell-cycle arrest, DNA repair or apoptosis. However, many of the pathological and clinical manifestations of A-T cannot be explained by defective DNA damage response signaling alone. It is now known that ATM is involved in a number of cytoplasmic processes, which influence cellular homeostasis and metabolism [15], and it is believed that many, if not most of the features of A-T are, in fact, caused by defective redox homeostasis [16, 17]. We are aware of only two other articles on ATM which reviewed (i) the role of ATM in the response to DNA breaks, and (ii) the molecular pathways leading to the clinical manifestations of A-T respectively [18, 19]. In the current review, we focused on the putative cardioprotective role of ATM signaling and how ATM deficiency can contribute specifically to the development of type 2 diabetes and cardiovascular disease.

Oxidative Stress In addition to its expression in the nucleus and cytoplasm, ATM has also been shown to localize to mitochondria, where it plays a role in mitochondrial functioning [20, 21]. Cardiomyocytes are particularly susceptible to mitochondrial dysfunction as it causes a reduction in energy production and contractility, changes in electrical properties and ultimately, cell death [22]. Cells derived from A-T patients or A-T

animals are constantly exposed to oxidative stress, the source of which is poorly characterized [23, 24]. Mitochondria isolated from A-T thymocytes have been shown to be swollen and have a disorganized structure. Additionally, decreased activity of complex I of the electron transport chain and changes in membrane potential were observed in these mitochondria. Furthermore, the clearance of damaged mitochondria by means of mitophagy was defective in A-T cells [21]. It is well-established that the mitochondrion is a major source of free radicals; when dysfunctional, these organelles generate increased amounts of reactive oxygen species (ROS) and it is proposed that this contributes to the oxidative stress observed in A-T cells (Fig. 1) [20, 21]. Excessive ROS levels can damage lipids and proteins and induce mitochondrial and nuclear DNA oxidation and single- and double-strand breaks [16]. In the presence of oxidative stress, activated ATM initiated an anti-oxidant response by shifting glucose metabolism from glycolysis to the pentose phosphate pathway (PPP) (Fig. 2) [38]. The oxidative phase of the PPP is the main source of NADPH, which is an important cofactor for anti-oxidants like glutathione reductase and cytochrome p450 reductase. It was shown that, by phosphorylating Hsp27, ATM increased the affinity of Hsp27 for glucose-6-phosphate dehydrogenase, which is the rate limiting enzyme of the PPP [38, 46]. In diabetic hearts, the activation of the PPP, and the consequent anti-oxidative effects, increased the viability and proliferation of cardiac progenitor cells [47]. This could be of particular clinical significance since cardiomyocytes, endothelial cells and fibroblasts are progressively lost via apoptosis and necrosis as a result of oxidative stress in failing human diabetic hearts [48]. Activated AMPK plays a regulatory role in both lipid and glucose metabolism in the heart and is believed to protect the structure and function of the diabetic heart as it increases autophagy [49, 50]. Additionally, inhibition of mTOR in type 2 diabetic mice (possibly mediated by a reduction in oxidative stress) leads to improved metabolism and cardiac function [51]. Treatment of cells with 0.01 mM H2O2 for a period of 60 min caused ATM to phosphorylate AMPK at threonine 172, both directly and via phosphorylation of the tumor suppressor, LKB1, at threonine 366. Upon activation, AMPK phosphorylates TSC2 at threonine 1271 and serine 1387 and the activated TSC2 inhibits mTORC1 [39], which in turn, leads to decreased protein synthesis and increased autophagy (Fig. 2). ATM was also able to inhibit mTORC1 activity under hypoxic conditions. ATM, activated by hypoxic stress, phosphorylates the transcription factor HIF-1α which leads to the transcription of REDD1. By binding with 14-3-3, REDD1 inhibits the association between 14-3-3 and TCS2, resulting in free TSC2 mediated inhibition of mTORC1 (Fig. 2) [40, 41]. Using three different ATM−/− cell models, Ousset et al. [23] found that the increased ROS levels associated with a

Cardiovasc Drugs Ther

Fig. 1 A number of metabolic and cardiovascular effects have been observed in the ATM-deficient state. Mitochondrial dysfunction, which contributes to elevated ROS levels, has been observed in ATM deficient cells [20, 21]. Elevated ROS associated with ATM-deficiency lead to increased biosynthesis of HIF-1, which results in an antioxidant response and maintained oxygen supply, but also insulin resistance and vascular dysfunction due to overexpression of GLUT1 and VEGF [23, 25–30]. ATM deficient mice have been found to have increased JNK levels, which lead to the serine phosphorylation of IRS-1 and ultimately contributes to the development of insulin resistance [31]. Increased JNK levels could also contribute to increased atherosclerosis through increased AP-1 activity and LPL expression [31, 32]. Other pathophysiological consequences of ATM-deficiency are metabolic disturbances consistent with the metabolic syndrome, such as dyslipidaemia (elevated

cholesterol, triglycerides and LDL proteins) and hypertension [33, 34]. Furthermore, the disruption of ATM-dependent phosphorylation of p53 has been shown to result in increased insulin resistance and atherosclerosis [35, 36]. Finally, ATM-deficient animals have been shown to have increased cardiac fibrosis and hypertrophy and βadrenergic receptor stimulation has been associated with increased cardiomyocyte apoptosis due to decreased PKB/Akt activity in these animals [37]. Abbreviations: AP-1 activator protein 1, ATM ataxia telangiectasia mutated, JNK c-Jun N-terminal kinase, DHA dehydroascorbic acid, GLUT1 glucose transporter 1, HIF-1 hypoxia inducible factor, IRS-1 insulin receptor substrate 1, LDL low-density lipoprotein, LPL lipoprotein lipase, PKB/Akt protein kinase B/Akt, ROS reactive oxygen species, VEGF vascular endothelial growth factor

deficiency in ATM protein led to an increased biosynthesis of both subunits of the HIF-1 transcription factor, which resulted in an overexpression of GLUT1 and vascular endothelial growth factor (VEGF). Although this initiates an antioxidant response, it may also contribute to two of the clinical manifestations observed in A-T, namely insulin resistance and vascular abnormalities. Overexpression of GLUT1 leads to increased basal uptake of glucose and dehydroascorbic acid (DHA) [23]. DHA becomes a ROS scavenger after it has been converted into ascorbic acid [25], whereas the overexpression of GLUT1 has been linked to the development of insulin resistance in skeletal muscle of mice and possibly contributes to the insulin resistance phenotype observed in A-T patients [26]. Vascular endothelial growth factor is one of the most important factors leading to angiogenesis [27] and overexpression of VEGF could possibly contribute to the telangiectasia seen in A-T patients. It has also been proposed that angiogenesis could contribute to the development of atherosclerosis or plaque instability, but this still needs to be confirmed [28]. Overexpression of VEGF is, however, also associated

with increased expression of myoglobin, an oxygen binding protein in cardiac and skeletal muscle [29]. Myoglobin maintains oxygen supply during high demand periods such as ischemia and exercise by releasing stored oxygen and may also act as a NO and ROS scavenger in cardiac and skeletal muscle (Fig. 1) [30].

Atherosclerosis and Metabolic Abnormalities Atherosclerosis and insulin resistance are both known to be major risk factors for the development of cardiovascular disease. Oxidative stress has been shown to contribute to the development of insulin resistance [52, 53], while atherosclerosis is associated with oxidative stress and DNA damage, both of which have been shown to activate ATM. A number of studies have shown that reduced expression of ATM gives rise to a clinical picture resembling the metabolic syndrome and that antioxidants or ATM activators improved some of the symptoms and signs [31, 54, 55]. There are also a number of

Cardiovasc Drugs Ther

Fig. 2 ATM has been shown to be activated by oxidative stress, hypoxia and insulin. In response to oxidative stress, ATM increases the rate of the pentose phosphate pathway in order to attain an antioxidant effect [38] and achieves increased autophagy and decreased protein synthesis through activation of the AMPK-mTORC1 pathway [39]. Increased autophagy and decreased protein synthesis are also achieved via HIF1α phosphorylation in response to hypoxia [40, 41]. By regulating an as yet unidentified phosphatase (possibly PP2A), ATM increases the phosphorylation of PKB/Akt in response to insulin stimulation, leading to increased protein synthesis and glucose uptake [42, 43]. ATM also directly phosphorylates 4E-BP1 in response to insulin stimulation, resulting in increased protein synthesis and it has also been shown that

ATM mediates insulin stimulated glucose uptake by phosphorylating AS160, causing GLUT4 externalization [44, 45]. Abbreviations: AS160 Akt substrate of 160 kDa, AMPK AMP-activated protein kinase, ATM ataxia telangiectasia mutated, eIF-4E eukaryotic translation initiation factor 4E, 4E-BP1 eukaryotic translation initiation factor 4E binding protein 1, GLUT4 glucose transporter 4, G6PD glucose-6-phosphotase dehydrogenase, Hsp27 heat shock protein 27, HIF-1α hypoxia inducible factor 1-alpha, LKB1 liver kinase B1, mTORC1 mammalian target of rapamycin complex 1, PPP pentose phosphate pathway, PKB/Akt protein kinase B/Akt, PP2A protein phosphatase 2A, REDD1 regulated in development and DNA damage response 1, TSC2 tuberous sclerosis 2

studies that suggested a protective role for ATM in both atherosclerosis and insulin resistance, which are discussed below. Increased JNK activity has been shown in aortas, macrophages, adipose tissue, skeletal muscle and livers of ATM deficient mice [31]. JNK-dependent phosphorylation of serine 307 of IRS-1 disrupts insulin signaling, leading to insulin resistance (Fig. 1). Consistent with this mechanism, mice deficient in JNK1 were protected from insulin resistance and obesity [56]. JNK also increases the activity of AP-1, a transcription factor that controls the expression of lipoprotein lipase (LPL) which is implicated in the development of atherosclerosis [31, 32] (Fig. 1). The oxidation of low-density lipoprotein serves as one of the first steps in the development of atherosclerosis [57]. More insight into the metabolic actions of the ATM protein was gained by the use of ATM haploinsufficient (ATM+/−/ ApoE−/−) mice. It was shown that these animals presented with elevated serum cholesterol, triglyceride and low-density lipoprotein levels and that a high fat diet induced increased atherosclerosis compared to control ATM+/+/ApoE−/− mice [33, 34]. The ATM haploinsufficient mice were also hypertensive, displayed abnormal carbohydrate and lipid metabolism and showed evidence of mitochondrial DNA damage and dysfunction (Fig. 1) [33]. In a follow-up study, it was showed that the use of the mitochondria-targeted anti-oxidant, MitoQ, was able to reverse some of the metabolic effects of ATM

haploinsufficiency: ATM+/−/ApoE−/− mice, treated with MitoQ for 14 weeks, presented with less fat accumulation and weight gain and decreased hyperglycemia, hypercholesterolemia and hypertriglyceridemia compared to untreated mice [55]. Chloroquine, which is an ATM activating drug, was able to decrease atherosclerotic lesions in ATM+/+/ ApoE−/− mice and decrease blood pressure, JNK activity, glucose and insulin levels in other animal models of insulin resistance [31]. Additionally, when Wip1 was deleted, and ATM consequently remained phosphorylated, the metabolic rate of apoE−/−Wip1−/− mice was accelerated, which led to reduced diet-induced fat deposition and a smaller number and size of atherosclerotic lesions compared to that of apoE−/−Wip1+/+ mice. This effect of Wip1-deficiency was achieved via an ATM-mTOR-dependent pathway [54].

Insulin Resistance It has been proposed that the insulin resistance observed in AT patients is the result of the disruption of several ATMdependent mechanisms [42]. One such mechanism that leads to the development of both insulin resistance and atherosclerosis, is the ATM/p53 pathway. ATM phosphorylates p53 at serine 15 (serine 18 in mice) [58]. Mice with a mutation on this site presented with increased expression of inflammatory

Cardiovasc Drugs Ther

cytokines and reduced expression of antioxidants [35]. These animals developed glucose intolerance and insulin resistance at 6 months of age, but not at 3 months and, consequently, Armata and colleagues [35] proposed that accumulated oxidative damage led to the disruption of glucose homeostasis. Treatment of high fat fed mice with chloroquine was shown to reduce atherosclerosis in wild-type mice, but not in p53-null mice, showing that the beneficial effects of ATM activation were dependent on the presence of p53 [36]. However, the downstream targets of the ATM/p53 pathway that confer protection, have not yet been fully elucidated (Fig. 1). In a study performed in ATM−/− mice, blood glucose levels and insulin secretion appeared to increase and decrease with age respectively, which could have been the result of dysfunctional pancreatic β-cells [59]. The mechanism for the decreasing insulin secretion has, however, not been established and it is proposed that it could be due to metastatic cancer, which is present in all ATM−/− mice at an advanced age, and not due to a direct involvement of ATM in insulin secretion [60]. However, ATM may play a role in β-cell homeostasis, as pancreatic ATM expression was increased upon lipid loading [31] and mice in which p53 could not be phosphorylated by ATM due to a mutation of serine 18, displayed hypertrophy of the pancreatic islets [35]. More direct roles for ATM in the insulin signaling network have also been shown. Insulin increased the kinase activity of ATM three-fold [61] and insulin-like growth factor-I (IGF-I) stimulation resulted in autophosphorylation of serine 1981, and therefore activation, of ATM in wild-type mice [62]. ATM regulates the expression of the IGF-I receptor (IGF-IR) in response to IGF-I by increasing the IGF-IR promotor activity [63]. It was further showed that ATM deficiency resulted in reduced IGF-I signaling as decreased IGF-I stimulated phosphorylation of PI3K, PKB/Akt, mTORC1 and S6K was observed in skeletal muscle of ATM+/− mice [62]. This is consistent with a role for ATM in IGF-I signaling downstream of IRS-I as IRS-I phosphorylation was not influenced by the ATM status [60, 62]. The ATM-deficiency disrupted the anti-apoptotic and pro-survival function of IGF-I in A-T cells. ATM-deficiency did, however, not influence the expression of the insulin receptor (IR) as it does with IGF-IR [42]. ATM, and specifically the PI3K domain of ATM, was shown to associate with PKB/Akt to form a complex in which PKB/Akt was phosphorylated at serine 473 in response to insulin stimulation [42]. Although this was an ATMdependent event, it is unlikely that ATM directly phosphorylated PKB/Akt, as serine 473 is not a S/T-Q motif [8, 43]. It was suggested that ATM increased PKB/Akt phosphorylation by regulating an unidentified okadaic acid-sensitive phosphatase such as PP1, PP2A or PP4-6 (Fig. 2) [43]. ATMdependent PKB/Akt phosphorylation at serine 473 is required for the subsequent threonine 308 phosphorylation, to achieve full activation of PKB/Akt [42, 60]. However, the

involvement of ATM in PKB/Akt activation is unsure as ATM was shown to play a role in insulin-stimulated PKB/ Akt activation in some cell types, but not in others [44]. In light of this, Ching and colleagues [62] hypothesized that the strength of the signal, which is weaker through IGF-IR and stronger through IR activation, determines whether or not ATM is required for full PKB/Akt activation. PKB/Akt-independent roles for ATM in insulin signaling have also been shown. Inhibition of ATM in L6 myotubes and mouse soleus muscle reduced insulin-stimulated phosphorylation of AS160, a Rab GTPase-activating protein which plays a key role in GLUT4 translocation to the cell surface (Fig. 2) [44, 45]. Consequently, reduced glucose uptake was observed, despite PKB/Akt and atypical PKC phosphorylation being unaffected in these cells [44]. ATM was found to play a role in glucose uptake mediated by both GLUT4 (insulin stimulated) and GLUT1 (basal). While GLUT4 is mainly found in adipose tissue, skeletal and cardiac muscle, GLUT1 is found in all tissue types where it plays a significant role in basal glucose uptake [26]. Different mechanisms contribute to reduced glucose uptake in response to inhibition or inactivation of ATM, as has been shown in L6 myoblasts. It was observed that GLUT4 translocation to the cell surface in response to insulin was reduced in L6 myoblasts containing kinase dead ATM compared to wild type L6 myoblasts [60]. Additionally, a decreased number of GLUT1 transporters were located at the cell surface of L6 myoblasts in which ATM was pharmacologically inhibited [64]. This resulted in a 48 % decrease in basal glucose uptake as well as a decrease in DHA transport. ATM phosphorylates GLUT1 at serine 490 [14], which was found to increase the interaction between GLUT1 and GIPC1 in order to achieve GLUT1 externalization to the cell surface [64]. It should be noted that the studies by Ousset et al. [23] and Andrisse et al. [64] seem to contradict each other as they found that a deficiency in functional ATM resulted in an increase in GLUT1 transcription and a decrease in GLUT1 at the cell surface respectively. It is possible that GLUT1 transcription is increased in order to compensate for the decreased externalization of GLUT1 in the absence of ATM, but more studies are needed to further elucidate the role of ATM in GLUT1 regulation. Insulin resistance and reduced glucose tolerance are contributing factors to the development of type 2 diabetes. Given the pivotal involvement of ATM in insulin signaling and glucose uptake, it does not come as a surprise that ATM is possibly involved in the action of metformin, one of the drugs most commonly used to treat type 2 diabetes. The ATM gene is present in a locus associated with the response to metformin treatment, as identified in a genome-wide association study. Variation in the ATM gene influenced the glycemic response to metformin and pharmacological inhibition of ATM has been shown to block the metformin-dependent activation of AMPK [65]. However, the involvement of ATM in the action of metformin remains a controversial topic [66].

Cardiovasc Drugs Ther

Protein Synthesis ATM was shown to play a role in protein synthesis as it phosphorylated 4E-BP1 on serine 111 in response to insulin in 293 T cells, contributing to the release of the translation initiation factor eIF-4E from 4E-BP1 (Fig. 2) [61]. Although this phosphorylation event was rapamycin-independent, rapamycinsensitive sites on 4E-BP1 must be phosphorylated before eIF4E is released [61]. The unbound eIF-4E is then free to bind to an mRNA N7-methylguanosine cap to initiate protein translation. Mice that do not contain the ATM gene was shown to have reduced body weights compared to ATM wild-type mice [67] and A-T cells are known to have a higher requirement for serum growth factors than wild type cells [61]. This is consistent with the involvement of ATM in protein synthesis, and consequently, growth-promotion. It would be interesting to investigate whether ATM plays a role in cardiac hypertrophy, as to our knowledge, no studies have been performed on the role of ATM on cardiac protein synthesis and growth promotion.

Cardiovascular The median lifespan of A-T patients is 20 years [68], which is too short for the development of cardiovascular problems resulting from deficient functional ATM protein expression. Consequently, in the past, the majority of research has focused on ATM functions related to more deleterious symptoms observed in A-T patients. However, from the above, it is evident that ATM plays a significant role in normal metabolism and stress signaling and, very importantly, defects in ATM signaling lead to a clinical picture similar to that of the metabolic syndrome, which is well known for increasing the risk for cardiovascular disease. Carriers of A-T do not display the severe clinical picture of A-T patients, however, they are not completely unaffected by ATM heterozygosity. In fact, it has been shown that A-T carriers have a higher mortality rate and die at an earlier age than non-carriers, possibly because ATM heterozygosity results in a more rapid progression of cancer and ischemic heart disease [2]. Many metabolic parameters are equally affected in ATM−/− and ATM+/− mice [69]. Animals fed a high fat diet have significantly reduced ATM protein levels, despite having two wildtype alleles for ATM [60]. This means that individuals who are wild-type for ATM could also experience metabolic dysfunction caused by diet-induced ATM deficiency. The heart primarily uses lipids as fuel, however, 10–40 % of the heart’s fuel is derived from glucose, and glucose becomes the main source of energy during ischemic conditions [70–72]. A disruption in glucose metabolism will therefore exert a notable effect on cardiac function, particularly during myocardial ischemia, and given the involvement of ATM in insulin signaling and glucose uptake (as described earlier), a

deficiency in ATM may possibly exacerbate cardiac dysfunction and enhance cell death. The cardiac effects observed in the absence of ATM, namely hypertrophy and fibrosis [37], have also been observed in diabetic hearts [73]. However, as far as we know, no information is currently available regarding myocardial substrate metabolism in ATM deficiency. Under basal conditions ATM is expressed in the heart, while β-adrenergic receptor stimulation was shown to increase ATM expression ~2.5 fold [37]. This could possibly be mediated by the transcription factor AP-1 as the ATM promoter contains a fat specific element that binds Fos-Jun complexes [74, 75]. Although acute β-adrenergic receptor stimulation has beneficial physiological effects, chronic βadrenergic receptor stimulation has harmful effects, eventually leading to cardiomyocyte apoptosis and cardiac remodeling [76]. Using ATM heterozygous knockout mice, it was found that the protein plays a protective role in chronic β-adrenergic receptor stimulated cardiomyocyte apoptosis as well as remodeling. Foster and coworkers showed that ATM deficient mice displayed increased cardiac fibrosis, hypertrophy and myocyte apoptosis compared to wild type mice, both before and after βadrenergic receptor stimulation (Fig. 1) [37]. Increased fibrosis was possibly mediated by the matrix metalloproteinases (MMPs) as increased MMP-2 expression and lower TIMP-2 levels were observed in isoproterenol-treated ATM deficient hearts [37, 77]. MMPs are proteolytic enzymes that degrade extracellular matrix and they have been implicated in myocardial extracellular remodeling when dysregulated [78]. Although chronic β-adrenergic receptor stimulation leads to cardiomyocyte apoptosis, both in the presence and absence of ATM, it was found that the signaling pathways involved differed, depending on the ATM status [77]. In wild type hearts, a p53- and a JNK-dependent mechanism was involved while decreased PKB/Akt activity contributed to β-adrenergic receptor stimulated apoptosis in ATM knockout hearts (Fig. 1). The ATM protein is also involved in modulation of cardiac remodeling following myocardial infarction as larger infarcts were found in ATM deficient mice 7 days post-infarction, which was associated with increased fibrosis and apoptosis [79].

Conclusion The ATM protein kinase regulates a vast number of substrates and thus has great potential as a therapeutic target. A number of studies have already shown that by inhibiting ATM, using ATM specific inhibitors, cancer cells become more sensitive to cancer treatments that promote double stranded DNA breaks [80]. The involvement of ATM in stress and metabolic signaling, as discussed in this review, has only recently been highlighted. It does, however, appear as if activation of ATM could potentially play a central role in protection against the development of cardiovascular disease. Known factors that

Cardiovasc Drugs Ther

either increase ATM expression or activation include βadrenergic receptor stimulation, chloroquine and insulin. As previously mentioned, the use of chloroquine has already been shown to have beneficial cardiovascular effects in animal models [31, 36]. However, chloroquine as well as the other factors mentioned can either have detrimental or unwanted accompanying effects in addition to activation of ATM, which makes them undesirable therapeutic targets. There is, therefore, a need to develop a novel drug that specifically activates ATM, with no additional effects. Recently, resveratrol, a phenolic compound known to be cardioprotective in animal models, was shown to activate ATM in an oxidizing environment [81]. It would be of interest to further investigate the effect of resveratrol on ATM and its potential involvement in protection against metabolic and cardiovascular complications. Conflict of interest The authors declare that they have no conflict of interest.

References 1. Savitsky K, Bar-Shira A, Gilad S, et al. A single ataxia-telangiectasia gene with a product similar to PI-3 kinase. Science. 1995;268:1749–53. 2. Su Y, Swift M. Mortality rates among carriers of ataxia-telangiectasia mutant alleles. Ann Intern Med. 2000;133:770–8. 3. Rasio D, Negrini M, Croce CM. Genomic organization of the ATM locus involved in ataxia-telangiectasia. Cancer Res. 1995;55:6053–7. 4. Swift M, Morrel D, Cromartie E, Chamberlin AR, Skolnick MH, Bishop DT. The incidence and gene frequency of ataxiatelangiectasia in the United States. Am J Hum Genet. 1986;39:573– 83. 5. Bakkenist CJ, Kastan MB. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature. 2003;421:499–506. 6. Yang DQ, Halaby M, Li Y, Hibmam JC, Burn P. Cytoplasmic ATM protein kinase: an emerging therapeutic target for diabetes, cancer and neuronal degeneration. Drug Discov Today. 2011;16:332–8. 7. Swift M, Chase C. Cancer and cardiac deaths in obligatory ataxiatelangiectasia heterozygotes. Lancet. 1983;321:1049–50. 8. Kim ST, Lim DS, Canman CE, Kastan MB. Substrate specificities and identification of putative substrates of ATM kinase family members. J Biol Chem. 1999;274:37538–43. 9. Guo Z, Kozlov S, Lavin MF, Person MD, Paull TT. ATM activation by oxidative stress. Science. 2010;330:517–21. 10. Uziel T, Lerenthal Y, Moyal L, Andegeko Y, Mittelman L, Shiloh Y. Requirement of the MRN complex for ATM activation by DNA damage. EMBO J. 2003;22:5612–21. 11. Pellegrini M, Celeste A, Didilippantonio S, et al. Autophosphorylation at serine 1987 is dispensable for murine ATM activation in vivo. Nature. 2006;443:222–5. 12. Goodarzi AA, Jonnalagadda JC, Douglas P, et al. Autophosphorylation of ataxia-telangiectasia mutated is regulated by protein phosphatase 2A. EMBO J. 2004;23:4451–61. 13. Sheeram S, Demidov ON, Hee WK, et al. Wip1 phosphatase modulates ATM-dependent signaling pathways. Mol Cell. 2006;23:757–64. 14. Matsuoka S, Ballif BA, Smogorzewska A, et al. ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science. 2007;316:1160–6.

15. Ditch S, Paull TT. The ATM protein kinase and cellular redox signaling: beyond the DNA damage response. Trends Biochem Sci. 2012;37:15–22. 16. Ambrose M, Gatti RA. Pathogenesis of ataxia-telangiectasia: the next generation of ATM functions. Blood. 2013;121:4036–45. 17. Semlitsch M, Shackelford RE, Zirkl S, Sattler W, Malle E. ATM protects against oxidative stress induced by oxidized low-density lipoprotein. DNA Repair. 2011;10:848–60. 18. Shiloh Y, Ziv Y. The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nat Rev Moll Cell Biol. 2013;14:197–210. 19. Stagni V, Santini S, Barila D. Molecular bases of Ataxia Telangiectasia: one kinase multiple functions. In: Puiu M, editor. Genet Disord. InTech; 2013. doi:10.5772/54045. 20. Ambrose M, Goldstine JV, Gatti RA. Intrinsic mitochondrial dysfunctions in ATM-deficient lymphoblastoid cells. Hum Mol Genet. 2007;16:2154–64. 21. Valentin-Vega YA, MacLean KH, Tait-Mulder J, et al. Mitochondrial dysfunction in ataxia-telangiectasia. Blood. 2012;199:1490–500. 22. Rosenberg P. Mitochondrial dysfunction and heart disease. Mitochondrion. 2004;4:621–8. 23. Ousset M, Bouquet F, Fallone F, et al. Loss of ATM positively regulates the expression of hypoxia inducible factor 1 (HIF-1) through oxidative stress. Cell Cycle. 2010;9:2814–22. 24. Watters DJ. Oxidative stress in ataxia telangiectasia. Redox Rep. 2003;8:23–9. 25. Arrigoni O, De Tullio MC. Ascorbic acid: much more than just an antioxidant. Biochim Biophys Acta. 2002;1569:1–9. 26. Buse MG, Robinson KA, Marshall BA, Mueckler M. Differential effects of GLUT1 or GLUT4 overexpression on hexosamine biosynthesis by muscles of transgenic mice. J Biol Chem. 1996;271:23197–202. 27. Hoeben A, Landuyt B, Highley MS, Wildiers H, Van Oosterom AT, De Bruijn EA. Vascular endothelial growth factor and angiogenesis. Pharmacol Rev. 2004;56:549–80. 28. Khurana R, Simons M, Martin JF, Zachary IC. Role of angiogenesis in cardiovascular disease: a critical appraisal. Circulation. 2005;112: 1813–24. 29. van Weel V, Deckers MML, Grimbergen JM, et al. Vascular endothelial growth factor overexpression in ischemic skeletal muscle enhances myoglobin expression in vivo. Circ Res. 2004;95:58–66. 30. Ordway GA, Garry DJ. Myoglobin: an essential hemoprotein in striated muscle. J Exp Biol. 2004;207:3441–6. 31. Schneider JG, Finck BN, Ren J, et al. ATM-dependent suppression of stress signaling reduces vascular disease in metabolic syndrome. Cell Metab. 2006;4:377–89. 32. Mead JR, Ramji DP. The pivotal role of lipoprotein lipase in atherosclerosis. Cardiovasc Res. 2002;55:261–9. 33. Mercer JR, Cheng KK, Figg N, et al. DNA damage links mitochondrial dysfunction to atherosclerosis and the metabolic syndrome. Circ Res. 2010;107:1021–31. 34. Wu D, Yang H, Xiang W, et al. Heterozygous mutation of ataxiatelangiectasia mutated gene aggravates hypercholesterolemia in apoE-deficient mice. J Lipid Res. 2005;46:1380–7. 35. Armata HJ, Golebiowski D, Jung DY, Ko HJ, Kim JK, Sluss HK. Requirement of the ATM/p53 tumor suppressor pathway for glucose homeostasis. Mol Cell Biol. 2010;30:5787–94. 36. Razani B, Feng C, Semenkovich CF. p53 is required for chloroquineinduced atheroprotection but not insulin sensitization. J Lipid Res. 2010;51:1738–46. 37. Foster CR, Singh M, Subramanian V, Singh K. Ataxia telangiectasia mutated kinase plays a protective role in β-adrenergic receptor-stimulated cardiac myocyte apoptosis and myocardial remodeling. Mol Cell Biochem. 2011;353:13–22. 38. Krüger A, Ralser M. ATM is a redox sensor linking genome stability and carbon metabolism. Sci Signal. 2011;4:pe17.

Cardiovasc Drugs Ther 39. Alexander A, Cai SL, Kim J, et al. ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS. Proc Natl Acad Sci U S A. 2010;107:4153–8. 40. Cam H, Easton JB, High A, Houghton PJ. mTORC1 signaling under hypoxic conditions is controlled by ATM-dependent phosphorylation of HIF-1α. Mol Cell. 2010;40:509–20. 41. DeYoung MP, Horak P, Sofer A, Sgroi D, Ellisen LW. Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling. Genes Dev. 2008;22:239–51. 42. Viniegra JG, Martínez N, Modirassari P, et al. Full activation of PKB/ Akt in response to insulin or ionizing radiation is mediated through ATM. J Biol Chem. 2005;280:4029–36. 43. Golding SE, Rosenberg E, Valerie N, et al. Improved ATM kinase inhibitor KU-60019 radiosensitizes glioma cells, compromises insulin, AKT and ERK prosurvival signaling, and inhibits migration and invasion. Mol Cancer Ther. 2009;8:2894–902. 44. Jeong I, Patel AY, Zhang Z, et al. Role of ataxia telangiectasia mutated in insulin signaling of muscle-derived cell lines and mouse soleus. Acta Physiol. 2010;198:465–75. 45. Sano H, Kane S, Sano E, et al. Insulin-stimulated phosphorylation of a rab GTPase-activating protein regulates GLUT4 translocation. J Biol Chem. 2003;278:14599–602. 46. Consentino C, Grieco D, Constanzo V. ATM activates the pentose phosphate pathway promoting anti-oxidant defense and DNA repair. EMBO J. 2011;30:546–55. 47. Katare R, Oikawa A, Cesselli D, et al. Boosting the pentose phosphate pathway restores cardiac progenitor cell availability in diabetes. Cardiovasc Res. 2013;97:55–6. 48. Frustaci A, Kajstura J, Chimenti C, et al. Myocardial cell death in human diabetes. Circ Res. 2000;87:1123–32. 49. Gray S, Kim JK. New insights into insulin resistance in the diabetic heart. Trends Endocrinol Metab. 2011;22:394–403. 50. Xie Z, He C, Zou MH. AMP-activated protein kinase modulates cardiac autophagy in diabetic cardiomyopathy. Autophagy. 2011;7: 1254–5. 51. Das A, Durrant D, Koka S, Salloum FN, Xi L, Kukreja RC. mTOR inhibition with rapamycin improves cardiac function in type 2 diabetic mice: potential role of attenuated oxidative stress and altered contractile protein expression. J Biol Chem. 2013;289:4145–60. 52. Bloch-Damti A, Bashan N. Proposed mechanisms for the induction of insulin resistance by oxidative stress. Antioxid Redox Signal. 2005;7:1553–67. 53. Evans JL, Maddux BA, Goldfin ID. The molecular basis for oxidative stress-induced insulin resistance. Antioxid Redox Signal. 2005;7:1040–52. 54. Le Guezennec X, Brichkina A, Huang YF, Kostromina E, Han W, Bulavin DV. Wip1-dependent regulation of autophagy, obesity, and atherosclerosis. Cell Metab. 2012;16:68–80. 55. Mercer JR, Yu E, Figg N, et al. The mitochondria-targeted antioxidant MitoQ decreases features of the metabolic syndrome in ATM+/ −/ApoE−/− mice. Free Radic Biol Med. 2012;52:841–9. 56. Hirosumi J, Tuncman G, Chang L, et al. A central role for JNK in obesity and insulin resistance. Nature. 2002;420:333–6. 57. Parthasarathy S, Steinberg D, Witzium JL. The role of oxidized lowdensity lipoproteins in the pathogenesis of atherosclerosis. Annu Rev Med. 1992;43:219–25. 58. Nakagawa K, Taya Y, Tamai K, Yamaizumi M. Requirement of ATM in phosphorylation of the human p53 protein at serine 15 following DNA double-strand breaks. Mol Cell Biol. 1999;19:2828–34. 59. Miles PD, Treuner K, Latronica M, Olefsky JM, Barlow C. Impaired insulin secretion in a mouse model of ataxia telangiectasia. Am J Physiol Endocrynol Metab. 2007;293:E70–4. 60. Halaby MJ, Hibma JC, He J, Yang DQ. ATM protein kinase mediates full activation of Akt and regulates glucose transporter 4 translocation by insulin in muscle cells. Cell Signal. 2008;20:1555–63.

61. Yang DQ, Kastan MB. Participation of ATM in insulin signaling through phosphorylation of eIF-4E-binding protein 1. Nat Cell Biol. 2000;2:893–8. 62. Ching JK, Luebbert SH, Collins RL, et al. Ataxia telangiectasia mutated impacts insulin-like growth factor 1 signaling in skeletal muscle. Exp Physiol. 2013;98:526–35. 63. Peretz S, Jensen R, Baserga R, Glazer PM. ATM-dependent expression of the insulin-like growth factor-I receptor in a pathway regulating radiation response. Proc Natl Acad Sci U S A. 2001;98:1676–81. 64. Andrisse S, Patel GD, Chen JE, et al. ATM and GLUT1-S490 phosphorylation regulate GLUT1 mediated transport in skeletal muscle. PLoS One. 2013;8:e66027. 65. Zhou K, Bellenguez C, Spencer CCA, et al. Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes: the GoDARTS and UKPDS Diabetes Pharmacogenetics Study Group and the Wellcome Trust Case Control Consortium 2. Nat Genet. 2011;43:117–20. 66. Birnbaum MJ, Shaw RJ. Drugs, diabetes and cancer: variation in a genomic region that contains the cancer-associated gene ATM affects a patient’s response to the diabetes drug metformin. Two experts discuss the implications for understanding diabetes and the link to cancer. Nature. 2011;470:338–9. 67. Barlow C, Hirotsune S, Paylor R, et al. ATM-deficient mice: a paradigm of ataxia telangiectasia. Cell. 1996;86:159–71. 68. Morrel D, Cromartie E, Swift M. Mortality and cancer incidence in 265 patients with ataxia-telangiectasia. J Natl Cancer Inst. 1986;77:89–92. 69. Shoelson SE. Banking on ATM as a new target in metabolic syndrome. Cell Metab. 2002;4:337–8. 70. Gertz EW, Wisneski JA, Stanley WC, Neese RA. Myocardial substrate utilization during exercise in humans. Dual carbon-labeled carbohydrate isotope experiments. J Clin Invest. 1988;82:2017–25. 71. Traegtmeyer H. Metabolism—the lost child of cardiology. J Am Coll Cardiol. 2000;36:1386–8. 72. Opie LH, Lopaschuk GD. Fuels: aerobic and anaerobic metabolism. In: Opie LH, editor. Heart physiology: from cell to circulation. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2004. p. 306–54. 73. Eguchi K, Boden-Albala B, Jin Z, et al. Association between diabetes mellitus and left ventricular hypertrophy in a multiethnic population. Am J Cardiol. 2008;101:1787–91. 74. Ghee M, Baker H, Miller JC, Ziff EB. AP-1, CREB and CBP transcription factors differentially regulate the tyrosine hydroxylase gene. Brain Res Mol Brain Res. 1998;55:101–14. 75. Gueven N, Keating K, Fukao T, et al. Site-directed mutagenesis of the ATM promoter: consequences for response to proliferation and ionizing radiation. Genes Chromosome Cancer. 2003;38:157–67. 76. Shizukuda Y, Buttrick PM, Geenen DL, Borczuk AC, Kitsis RN, Sonnenblick EH. β-adrenergic stimulation causes cardiocyte apoptosis: influence of tachycardia and hypertrophy. Am J Physiol. 1998;275:H961–8. 77. Foster CR, Zha Q, Daniel LL, Singh M, Singh K. Lack of ataxia telangiectasia mutated kinase induces structural and functional changes in the heart: role in β-adrenergic receptor-stimulated apoptosis. Exp Physiol. 2012;97:506–15. 78. Spinale FG. Matrix metalloproteinases: regulation and dysregulation in the failing heart. Circ Res. 2002;90:520–30. 79. Foster CR, Daniel LL, Daniels CR, Dalal S, Singh M, Singh K. Deficiency of ataxia telangiectasia mutated kinase modulates cardiac remodeling following myocardial infarction: involvement in fibrosis and apoptosis. PLoS One. 2013;8:e83513. 80. Vecchio D, Frosina G. Targeting the ataxia telangiectasia mutated protein in cancer therapy. Curr Drug Targets. 2014;PMID 25382204. 81. Lee JH, Guo Z, Myler LR, Zheng S, Paull TT. Direct activation of ATM by resveratrol under oxidizing conditions. PLoS One. 2014;9: e97969.

ATM protein kinase signaling, type 2 diabetes and cardiovascular disease.

The ataxia-telangiectasia mutated (ATM) protein kinase is well known to play a significant role in the response to double stranded DNA breaks in the n...
675KB Sizes 1 Downloads 5 Views