Life Sciences 121 (2015) 97–103

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Review article

The role of Pyruvate Dehydrogenase Complex in cardiovascular diseases Wanqing Sun, Quan Liu, Jiyan Leng, Yang Zheng, Ji Li ⁎ Division of Cardiovascular Medicine, The First Hospital of Jilin University, Changchun 130021, China

a r t i c l e

i n f o

Article history: Received 28 August 2014 Accepted 28 November 2014 Available online 11 December 2014 Keywords: Pyruvate Dehydrogenase Complex Glucose metabolism Heart disease

a b s t r a c t The regulation of mammalian myocardial carbohydrate metabolism is complex; many factors such as arterial substrate and hormone levels, coronary flow, inotropic state and the nutritional status of the tissue play a role in regulating mammalian myocardial carbohydrate metabolism. The Pyruvate Dehydrogenase Complex (PDHc), a mitochondrial matrix multienzyme complex, plays an important role in energy homeostasis in the heart by providing the link between glycolysis and the tricarboxylic acid (TCA) cycle. In TCA cycle, PDHc catalyzes the conversion of pyruvate into acetyl-CoA. This review determines that there is altered cardiac glucose in various pathophysiological states consequently causing PDC to be altered. This review further summarizes evidence for the metabolism mechanism of the heart under normal and pathological conditions including ischemia, diabetes, hypertrophy and heart failure. © 2014 Elsevier Inc. All rights reserved.

Contents Introduction. . . . . . . . . . . . . . . . . . . . Structure of PDHc. . . . . . . . . . . . . . . Regulation of PDHc . . . . . . . . . . . . . . Cardiac need of glucose . . . . . . . . . . . . . . Expression of PDH in normoxic and pathological heart Ischemia and reperfusion . . . . . . . . . . . Hypertrophy . . . . . . . . . . . . . . . . . Diabetic heart . . . . . . . . . . . . . . . . Heart failure . . . . . . . . . . . . . . . . . Effects of pathological conditions on heart via PDH . . Glucose and insulin . . . . . . . . . . . . . . Dichloroacetate (DCA) . . . . . . . . . . . . L-carnitine and propionyl L-carnitine . . . . . . Angiotensin II . . . . . . . . . . . . . . . . Carnitine palmitoyltransferase I (CPT I) inhibitors Conclusion . . . . . . . . . . . . . . . . . . . . Future prospects . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . .

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Introduction

⁎ Corresponding author at: Division of Cardiovascular Medicine, The First Hospital of Jilin University, Changchun 130021, China. Tel no.: 86 431 8878 2217 E-mail address: [email protected] (J. Li).

http://dx.doi.org/10.1016/j.lfs.2014.11.030 0024-3205/© 2014 Elsevier Inc. All rights reserved.

Researching the mechanism of cardiovascular disease from a metabolic point of view requires significant effort and workforce and is a complex research topic that has required a large initiative in the healthcare industry. The primary purpose of this study is to discuss the role of Pyruvate Dehydrogenase Complex (PDHc) in cardiovascular

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diseases. PDHc, a multi-enzyme complex located in the mitochondrial matrix, plays a key role in aerobic energy metabolism. This multienzyme complex occupies a central crossroad of glycolysis, and the tricarboxylic acid cycle by catalyzing the oxidative decarboxylation of pyruvate to form acetyl CoA [79], which is depicted in Fig. 1. The rest of the paper is organized as follows; we categorize the main body into four categories: the first two sections introduce the structure and regulation of PDHc. In addition, we discuss why glucose is critical to the heart and the important role that PDHc plays in glucose oxidation. The next two sections demonstrate the expression of PDHc in the pathological heart and the factors, which influence the level, and activity of PDHc. Structure of PDHc In this section, the structure of PDHc is described. PDHc is composed of three catalytic components, namely, Pyruvate Dehydrogenase (E1), Dihydrolipoamide Acetyltransferase (E2), and Dihydrolipoamide Dehydrogenase (E3) [72]. At the peripheral of PDHc's complex structure are 20 to 30 copies of E1, 60 copies of E2, 6 copies of E3, and one binding protein known as Dihydrolipoamide Dehydrogenase and lastly, two regulatory enzymes, namely, a family of PDH kinases and a family of PDH phosphatases.[72]. The PDHc complex also requires five different coenzymes: CoA, NAD+, FAD+, lipoic acid and Thiamine Pyrophosphate (TPP). Three of the coenzymes of the complex – TTP, lipoic acid, and FAD +, are tightly bound to enzymes of the complex and two – CoA and NAD+ − are employed as carriers of the products of PDHc activity [80]. These components of PDHc are illustrated in Fig. 1. The net result of the reactions of the PDHc is: þ

þ

Pyruvate þ CoA þ NAD → CO2 þ acetyl‐CoA þ NADH þ H : Regulation of PDHc PDHa is the active form of PDHc and PDHb is the inactive form, there is no full name, when PDHc is active, it means it is dephosphorylated, when PDH is inactive, it means it is phosphorylated. Regulations are the activity which convert PDHc between its dephosphorylated active form PDHa and phosphorylated inactive PDHb [52,103]. Dephosphorylation of PDHc is catalyzed by two Pyruvate

Dehydrogenase Phosphate Phosphatases (PDPs), which are variably expressed in different tissues [29,35,74,75,82]. The first PDP, PDP1, is stimulated by calcium (Ca2+) ions mainly in the Ca2+ sensitive tissues [35]. The second PDP isoform, PDP2, is found in liver and adipose tissues [35]. In the adipose tissue, insulin reduces the concentration dependence of PDP activity [9] for magnesium (Mg2+) ions [99]. This causes PDHc to become phosphorylated and therefore inactivated by a family of four PDH kinases (PDK1–4), namely, PDH kinase1, PDH kinase2, PDH kinase3 and PDH kinase4 [32,95]. As a result, PDH phosphatase activates the enzyme complex. PDH kinase (PDK) consists of two dissimilar subunits α and β. Kinase activity resides in the α-subunit, where its selective proteolytic cleavage happens, leading to the loss of activity. The β-subunit is a regulatory subunit. Kinase and phosphatase activities are all activated by elevated [acetyl-CoA/CoA] and [NADH/NAD+] ratios [4, 10,95] and inhibited by elevated Adenosine Diphosphate (ADP) levels [81] and the drug dichloroacetate [4,108,109] in the mitochondrial matrix. Also, activity of this complex enzyme is regulated by a host of factors, including physiological concentration of Ca2+ ([Ca2+]), [Mg2+], which inhibits PDH kinase and active PDH phosphatase [16,31]. Under pathological conditions composed of ischemia and neurodegenerative disorders, PDH could be a target for damage and subsequent inaction attributed to three factors: The complexity of the multitude of subunits, strict cofactor requirements, and stringent regulation of the PDHc. Cardiac need of glucose In the well-perfused heart, glucose accounts for less than 25% of the energy production, with the majority of energy being derived from fatty acid oxidation (60–90% of ATP from fatty acid oxidation, 10–40% from glucose and lactate oxidation in the tricarboxylic acid (TCA) cycle through the PDH, and less than 2% from glycolysis) [22,87,93]. Because of the limited storage capacity for fatty acids and glucose in the heart, the heart needs to change in energy demands in different situations. The main purpose of the heart is to tightly regulate the pathways of oxidation of both fatty acids and glucose. For example, fatty acid oxidation is the primary energy source for the adult heart, whereas the fetal heart relies more on glucose metabolism [57]. Myocardial ischemia most frequently occurs in coronary artery disease patients who do not have the normal coronary flow needed to meet the demands for contractile power, myocardial Adenosine Triphosphate (ATP) synthesis, and oxygen consumption. Previous studies

Fig. 1. Mechanisms regulating the Pyruvate Dehydrogenase Complex by the PDH kinase/phosphatase system, interconverting between the active and inactive forms.

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in coronary artery disease patients show that several actions take place when angina is induced by cardiac pacing; these include a switch from myocardial lactate uptake to lactate production, depression of the S–T segment, and chest pain [64,93]. Thus, during a demand induced myocardial ischemia, there is a high rate of anaerobic glycolysis despite a high rate of residual myocardial oxygen consumption. There is a relationship between myocardial recovery during postischemic reperfusion and glycolytic activity. The rapid recovery of the intracellular pH is not enough to restore cardiac function because there is a significant increase in intracellular Na+ and Ca++, which contributes to the state of post-ischemic contractile dysfunction [49,64,97]. And although the ATP contents of glucose are similar to pyruvate during reperfusion, the recovery of contractile function in isolated rabbit hearts with glucose was superior [43]. Furthermore, recovery of Ca+ homeostasis [42] and metabolic activity [41] were better in glucosereperfused hearts compared with reperfusion with pyruvate in combination with iodoacetate (IAA), an irreversible inhibitor of glycolysis. Several studies have shown that increased glucose oxidation relative to fatty acids improves blood flow outcome after myocardial ischemia and reperfusion. During myocardial ischemia–reperfusion injury, fatty acid utilization is not beneficial to the heart. The cardiac efficiency is reduced when fatty acids are the predominant energy substrate while glucose oxidation rates are low [51,59]. Glucose oxidation is more ‘oxygen efficient’, with a complete switch to glucose reducing oxygen demand by 11–13% [50]. Notably, persuasive data from the same studies indicated that the circulating glucose level was a strong predictor of clinical outcomes [63], emphasizing the importance of disturbed glucose homoeostasis in myocardial ischemic heart disease. Expression of PDH in normoxic and pathological heart Ischemia and reperfusion In the heart, PDH is the rate-limiting enzyme for glucose oxidation which converts pyruvate to acetyl-CoA. During myocardial ischemia, there is a switch from net lactate uptake to net lactate production. The switch activates glycolysis thereby increasing the ratio of NADH to NAD+, and impairing the flux through PDH [7,53,55]. The flux of pyruvate through PDH is a key determinant of the rate of lactate production [55]. Besides the phosphorylation state of PDH, studies in myocardial ischemia and reperfusion on dogs and pigs show that an increase in the NADH to NAD+ and acetyl-CoA to free CoA ratios inhibits the rate of pyruvate flux through PDH at a given phosphorylation state [14,40,113]. This in turn reduces the rate of pyruvate and glucose oxidation [55]. There are also studies that have pointed out that during the first 10 to 15 min of reperfusion following transient ischemia in the heart, PDH is predominantly in the phosphorylated inactive form [45,47,73]. Despite the disparity in evidence regarding PDH activity, cardiac efficiency and recovery of contractile function in post-ischemic hearts can be improved by pharmacological stimulation of PDH [5,91], or the infusion of pyruvate [17,62,107]. There is already a substantial body of evidence demonstrating that activating PDC through inhibiting PDK activity pharmacologically is a useful therapeutic target for avoiding heart diseases such as cardiomyopathy, particularly during heart surgery, and partial ischemia [8,15,24,54,59,61,71,92,96,98,110,117]. In general, pharmacological interventions that increase glucose oxidation and thus the fraction of glucose-derived pyruvate oxidized and improved functional recovery of the heart during reperfusion [44,53,92]. Activating PDC in post-ischemic myocardium yields variable results due to the condition of reperfusion [26,98]. There are two main conditions that influence the consequence of reperfusion; the length of time of the coronary flow shut down and the substrate used in the reperfusion media. In a recent study from Ussher et al. [102], both MCD−/− mice (Malonyl CoA Decarboxylase, a key enzyme in the regulation of fatty

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acid oxidation [25,102–104], a potent endogenous inhibitor of the rate-limiting enzyme for mitochondrial fatty acid uptake — carnitine palmitoyltransferase 1 (CPT1) [65]) and PDHK 4-deficient (PDHK4−/−) mice, which have enhanced myocardial PDH activity. Inhibiting mitochondrial fatty acid uptake and oxidation via genetic deletion of MCD [20] translates to a reduction in the infarct size following ischemia/ reperfusion in vivo. The study also concluded that enhanced PDH activity and subsequent glucose oxidation, which is secondary to the inhibition of fatty acid oxidation, might be responsible for the decrease in infarct size. Also, PDHK4−/− mice, which lose the primary kinase responsible for inhibiting PDH in the heart showed a decrease in the infarct size following ischemia/reperfusion in vivo [20]. Hypertrophy In animal models, the hypertrophied heart possesses an altered metabolic profile that is similar to a fetal heart with a reduced fatty acid and an increased preference for carbohydrate sources [6,19,78]. Without correspondingly increased rates of pyruvate, enhanced glucose oxidation cannot fulfill the energy production by improving the level of rates of glycolysis [1–3,21]. However, compared with normal hearts, glucose oxidation is actually lower in hypertrophied hearts [1]. Consequently, the fractional oxidation of glucose to glycolysis, is lower in hypertrophied hearts by 10 to 15% than in normal hearts which have a level of 20 to 25%. In addition, increasing the production of pyruvate by accelerating rates of glycolysis would reduce the higher rates of glucose oxidation by increasing the activation of the Pyruvate Dehydrogenase Complex [72,77]. But in Lydell et al. [60], the authors contrasted with a significantly lower fractional oxidation of pyruvate in cardiac hypertrophy; the total PDC activity was slightly higher in hypertrophied hearts than that in the control hearts [60]. It was therefore concluded that decreased fractional oxidation of glucose in hypertrophied hearts cannot be easily explained by the reduction of the activity of PDHC. Based on transcription of PDK4 which is stimulated by the nuclear fatty acid receptor PPAR-α [36,94,112], increased PPAR-α activity in the heart can cause cardiomyopathy [23,115]. Finck et al. [23] showed that selective overexpression of PPAR-α in the heart caused ventricular hypertrophy and systolic dysfunction. In another research, it was concluded that ligand-mediated reactivation of PPAR-α caused contractile dysfunction and heart failure in the pressure overload model ([115]). And recently, Zhao et al. [116] observed a marked inhibition of PDC activity in the hearts of transgenic mice through overexpressing PDH kinase 4 [116]. In this later report, the authors demonstrated that selective overexpression of PDK4 in the heart was sufficient to alter substrate utilization by increasing cardiac fatty acid utilization and decreasing carbohydrate in energy metabolism. Further, it was observed that overexpression of PDK4 alone was sufficient to cause metabolic inflexibility and to exacerbate preexisting cardiomyopathy caused by chronic activation of the calcineurin signaling pathway [116]. Other related studies include Sidhu et al. [88] who used a heart/ skeletal muscle-specific PDC knockout (H/SM-PDCKO) mouse model with complete absence of PDH activity in null male mice and 50% reduction in heterozygous female mice [88]. Their results revealed that PDC null mutation in male mice resulted in death in less than seven days after weaning from a rodent laboratory chow diet. Although weaning the male mice from a high-fat diet prevented death, myocyte hypertrophy and left ventricular dysfunction still developed. [86]. The authors reported that there was no significant change in PDH in the hypertrophied group, but the fraction of PDH in the active form significantly decreased from 61 ± 1% in controls to 36 ± 1% (P b 0.05). This study reports for the first time that concomitant with the development of compensated hypertrophy, there is a decrease in the fraction of PDH in the active form, which indicates that myocardial substrate delivery to the mitochondria may be impaired in hypertrophy, consequently leading to energy depletion observed in heart failure.

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Diabetic heart

Dichloroacetate (DCA)

Under ambient metabolic conditions, diabetic animals exhibited several conditions, namely, elevated plasma arterial glucose and Free Fatty Acid (FFA) concentrations, decreased tissue concentrations of GLUT-4 and GLUT-l proteins, and decreased both active and total PDH activities [30]. The acetyl CoA-to-CoASH ratio tended to be higher in the diabetic animals, which may partially explain the decrease in percent active PDH in the diabetic group [30]. Hall et al. [30] tested the diabetic animals and found a defect in myocardial pyruvate oxidation, with depressed lactate uptake and Pyruvate Dehydrogenase activity under diabetic conditions. In their isolated rat heart model, they reported decreases in myocardial glucose transport, glycolysis, and glucose oxidation. Compared with the non-diabetic group, the initial values for total PDH activity, active PDH, and percent active PDH were significantly decreased by 25%, 44%, and 26% in diabetic rats respectively. The percent active PDH was observed to be correlated with tracer-measured lactate uptake. These findings suggest that a decrease in PDH levels in diabetes corresponds to impaired lactate uptake and oxidation. Furthermore, pharmacological activation of PDH in isolated perfused diabetic hearts results in an increase in glucose oxidation and improved contractile function [24].

DCA, the PDH kinase inhibitor, responsible for maintaining PDH in the dephosphorylated active form and increasing the oxidation of pyruvate [89,108] was reported in a study which used 13C NMR analysis of substrate oxidation in post-ischemic rabbit hearts [47]. In addition, DCA has been shown to bring about inhibition of fatty acid oxidation, presumably by shuttling acetyl CoA groups out of the mitochondria, which eventually can lead to an increase in malonyl CoA concentration and the inhibition of CPT I and mitochondrial fatty acid uptake [83,91]. Further, DCA stimulates glucose and lactate oxidation, and dramatically improves recovery of cardiac work following ischemia [48,53,59,68,76,105]. DCA is also capable of reducing H+ production from glucose metabolism during reperfusion so that DCA has another effect that decreases the imbalance between glycolysis and glucose oxidation. Recent studies have proved that by decreasing the fate of H+, the recovery of mechanical function and cardiac efficiency in the post-ischemic heart can be improved [53,59]. While highly beneficial for myocardial ischemia, DCA has toxic side effects [90,114], mainly because of lactate build-up during heart ischemia. Another limitation of DCA is its low potency blood levels and short half-life [89]. L-carnitine

Heart failure Heart failure is a rather complex clinical syndrome that is generally defined as an impaired ability of one or two ventricles to fill with and eject blood [38]. The etiology of heart failure is broadly divided into two main causes: Coronary artery disease and hypertension [66,67]. Metabolic perturbations in the heart play a key role in the pathogenesis of heart failure [58,70]. Prior research showed that myocardial levels of messenger RNA (mRNA) for key enzymes of the fatty acid β-oxidation pathway and also carbohydrate metabolism (glucose transporters, glyceraldehyde phosphate dehydrogenase, and Pyruvate Dehydrogenase) were decreased in dogs with end stage heart failure compared with normal myocardium [46]. There are other important mechanisms that play important roles in the development of heart failure including abnormal signal transduction [39], mitochondrial dysfunction, and disrupted intracellular Ca2 + handling [13]. Most of these mechanisms affect utilization of energy substrates such as PDH. As such, heart failure appears to suppress the transcription of a broad array of metabolic enzymes and does not selectively down-regulate the expression of fatty acid β-oxidation enzymes nor does it up-regulate glycolysis or pyruvate oxidation.

Effects of pathological conditions on heart via PDH There are several ways to protect the heart from a pathological situation in metabolism level. One is inhibiting fatty acid oxidation and the second is increasing glucose oxidation, or directly activating PDH activity. In this section, some effects which work on the heart through the third way will be introduced.

Glucose and insulin In the case of an acute myocardial infarction, the therapeutic solution for recovery is elevating glucose levels to enhance cardiac performance during ischemia. The beneficial effects of hyperglycemia and hyperinsulinemia decrease plasma FFA concentration and elevated insulin levels and result in an increase in PDH activity, less lactate and H+ accumulation. Preferential use of external pyruvate over glucose or lactate is enhanced by insulin or DCA [54]. The ability of insulin to increase PDCa due to activating PDP2, which is also decreased during starvation [37].

and propionyl L-carnitine

L-carnitine, which is the active form of carnitine, is not only required for the transport of fatty acid from the intermembranous space in the mitochondria to the mitochondrial matrix during the breakdown of lipids for the generation of metabolic energy, but also plays a role in regulating pyruvate oxidation in the heart, consequently leading to an increase in glucose oxidation [11,12]. El Alaoui-Talibi et al. found that adding propionyl-L-carnitine in rat diet significantly improved myocardial performance [21]. One of the ways L-carnitine increases fatty acid oxidation is by decreasing acetyl-CoA levels. A decrease in acetyl-CoA levels consequently promotes pyruvate oxidation through PDHa. Moreover, in Lopaschuk et al.'s [56] research, the study group with L-carnitine supplement in the diet clearly improved mechanical activity in ischemic and reperfused hearts [56]. Other researchers also reported that individuals who had not been treated with L-carnitine supplements almost invariably developed severe cardiac disease [84,106].

Angiotensin II In clinical treatment, it is common to use the Renin–Angiotensin System (RAS) blockade to treat heart failures. This is because RAS is a well-known mediator of cardiac hypertrophy and heart failure (1991, [27]). Insulin resistance is both associated with heart failure and the development of cardiac hypertrophy [18,28,100,111] and therefore causes disruptions in cardiac energy metabolism [58,93]. Mori et al. [69] studied the metabolic perturbations and insulin response in an ANG II-induced hypertrophy model and concluded that the ANG IItreated mice's hearts showed a lower response to insulin. Also, a reduction of glucose oxidation was associated with increased PDK4 levels. ANG II also reduced PDH activity via acetylation of PDH complex, as well as increased phosphorylation in response to increased PDK4 levels [69]. The study further showed that deletion of PDK4 not only prevented ANG II-induced diastolic dysfunction, but also normalized glucose oxidation to basal levels. More importantly PDK4 deletion was also associated with the prevention of diastolic dysfunction. Carnitine palmitoyltransferase I (CPT I) inhibitors CPT I is the key enzyme for altering the metabolic substrate utilization via inhibiting fatty acid uptake in the glucose–fatty acid cycle although inhibition of CPT I is another way of reducing myocardial fatty acid oxidation via inhibiting fatty acid uptake in the glucose–fatty acid

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cycle, relieving fatty acid inhibition of PDH, and increasing the oxidation of glucose [33,34,56], and lactate [85]. These above will improve the cardiac function during recovery from ischemia, and also prevent the impairment in contractile function. During the test of the hypothesis that an increase in work would result in a decrease in the levels of malonyl CoA using a potent inhibitor of carnitine palmitoyltransferase I (CPT I), Higgins et al. found that malonyl CoA decreased significantly with dobutamine in both the control group and the dobutamine-infusion group, providing a possible mechanism for increased fatty acid oxidation through relieved inhibition on CPT I [34]. Conclusion It is clearly discussed that alteration in energy metabolism has emerged as an important factor responsible for ischemia/reperfusion, diabetes, poor contractile function of hypertrophy and heart failure. The beneficial functional effect of stimulating glucose oxidation through PDH in hypertrophied and post ischemia hearts indicates that a limitation of glucose oxidation is particularly relevant to contractile dysfunction of such hearts. Modulation of myocardial metabolism is a novel attractive approach for protecting cardiac cells and improving performance of dysfunctional myocardium. PDH is central to both mitochondrial fuel metabolism, and to organismal health and survival. Deficiency of the complex either by the imposition of congenital or acquired diseases, displays various pathological conditions. Future prospects The challenge that we now face is the application of the discussed findings from animal studies to humans, and the identification of therapeutic solutions that can be applied to patients. For example, in the many experiments discussed above, the activation of PDH can be monitored by 13C NMR spectroscopy on the metabolic and functional paradigms of pharmacological myocardium in an isolated perfused heart model. The actual conditions in vivo are not likely to offer the opportunity for such precise manipulation of substrate supply. Currently, the challenge is to find a way to monitor in human bodies. Furthermore, the changes in the non-energy producing pathways of substrate metabolism may equally play important roles in the disease mechanisms. As such, these too deserve equal attention in our future research. Conflict of interest statement All authors have no conflict of interest.

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