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| DISEASE MECHANISMS IN PVD |
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| Year : 2009 | Volume
: 1
| Issue : 3 | Page : 163-166 |
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Impaired oxidative metabolism and enhanced glycolysis in right ventricular hypertrophy: The warburg effect
Lin Piao1, Peter T Toth1, Dalia Urboniene1, Stephen L Archer2
1 Department of Medicine, University of Chicago, Chicago, Illinois, USA
2 Section of Cardiology, University of Chicago, Chicago, Illinois, USA
| Date of Web Publication | 27-Jul-2009 |
Correspondence Address:
Stephen L Archer
Harold Hines Jr. Professor of Medicine, Chief of Cardiology, University of Chicago, 5841 South Maryland Avenue, (MC6080), Chicago, Illinois, 60637
USA
  | 5 |
DOI: 10.4103/0974-6013.54757
 Abstract | | |
Right ventricular hypertrophy (RVH) is a serious clinical problem that complicates many disease processes, including pulmonary arterial hypertension (PAH). PAH is a lethal syndrome of pulmonary hypertension due to the obstruction, obliteration, and constriction of small pulmonary arteries. One of the most important prognostic factors in PAH is RV function. Nowadays, surprisingly little work has been done on the change in RV function by PAH. Recent evidence suggests that there is a change in metabolism in PAH, reminiscent of the Warburg effect (i.e. increased glycolysis and decreased glucose oxidation occurs despite abundant PO 2 ). In PAH, the increased expression of pyruvate dehydrogenase kinase (PDK) may inhibit pyruvate dehydrogenase (PDH), limiting oxidative metabolism. PDK-4, a key regulator of glucose metabolism, is activated in monocrotaline (MCT)-induced RVH. This phosphorylates and inhibits PDH, thereby decreasing oxidative metabolism. There appears to be a compensatory increase glycolysis in RVH. This is associated with an increase in the expression of the glucose transported, GLUT4. RVH-related changes in metabolism may alter cardiac repolarization, which could predispose PAH patients to arrhythmia and decreased contractile function. We have noted altered shape and duration of cardiac action potential (AP) repolarization in RVH (largely dependent on dynamic changes in K + channel expression). Our preliminary data show that there is AP prolongation in RVH. We propose the concept that altered metabolism may alter ion channel expression in RVH and that this in turn causes AP prolongation. Based on our preliminary data and the literature, we hypothesize that a Warburg effect occurs in RVH and suggest that this may constitute a new therapeutic target.
How to cite this article:
Piao L, Toth PT, Urboniene D, Archer SL. Impaired oxidative metabolism and enhanced glycolysis in right ventricular hypertrophy: The warburg effect. PVRI Review 2009;1:163-6 |
How to cite this URL:
Piao L, Toth PT, Urboniene D, Archer SL. Impaired oxidative metabolism and enhanced glycolysis in right ventricular hypertrophy: The warburg effect. PVRI Review [serial online] 2009 [cited 2013 May 21];1:163-6. Available from: http://www.pvrireview.org/text.asp?2009/1/3/163/54757 |
| Introduction | |  |
Pulmonary arterial hypertension (PAH) is a lethal syndrome caused by vascular obstruction and vasoconstriction. One of the major causes of mortality in PAH is right ventricular hypertrophy (RVH). Chronic pressure overload, similar to that of PAH, stimulates right ventricular (RV) hypertrophy in an attempt to compensate for the increased afterload. However, RVH is rarely fully compensatory and may come at the price of causing RV ischemia, RV contractile dysfunction and eventually RV failure. [1] Surprisingly, little is known about the specific mechanisms underlying RVH and RV dysfunction in PAH, a deficiency that inspired a call for research in this area by the National Heart, Lung, and Blood Institute working group (NIH). [2] While the obvious approach to reducing RVH and RV failure is to treat the underlying pulmonary arterial disease, recent experimental evidence suggests that the RV can be therapeutically targeted in PAH. [3]
Etiology of PAH
PAH is a disease characterized by a progressive increase in pulmonary arterial pressure caused by obstructed and constricted small pulmonary arteries. PAH predominantly affects young women and has a 15% 1-year mortality rate despite modern therapy. [4] Due to lack of data on PAH in Africa and Asia and because of the insensitivity of history and physical examination, the reported prevalence of idiopathic PAH (1/1,000,000) is likely an underestimation. [5] Many abnormalities occur in PAH that contribute to the vascular obstruction, vasoconstriction and increased overload, including endothelial dysfunction, [6] bone morphogenetic protein receptor-2 gene mutations, [7] inappropriate, normoxic activation of hypoxia-inducible factor-1 α (HIF-1α) and pyruvate dehydrogenase kinase (PDK), [8],[9] depressed expression of O 2 -sensitive voltage gated K + channel (Kv1.5 and Kv2.1). [2] Our laboratory has identified morphologic and functional abnormalities of mitochondria in PASMC that lead to an altered redox state and hence the activation of HIF-1α and downregulation of Kv channels. [10] This abnormal mitochondria-ROS-HIF-1α-Kv1.5 pathway in PAH can be successfully treated by the PDK inhibitor, dichloroacetate (DCA). DCA helps the metabolism to return to normal by inhibiting PDK. The return of oxidative metabolism inhibits PASMC proliferation, enhances apoptosis and thereby improves hemodynamics and survival in experimental PAH. [3]
RVH and the metabolic switch
While the metabolic changes in normoxic RVH have not been studied, there are parallels to left ventricular hypertrophy (LVH). In LVH, instead of undergoing glucose oxidation, glycolysis is accelerated, which in turn increases lactate production. [11] Increased concentrations of adenosine di- and mono- phosphates (ADP and AMP) activate the AMP-activated protein kinase (AMPK) cascade. [12] Positron emission tomography confirms the development of a glycolytic phenotype in hypertrophied myocardium, as demonstrated by increased fluorodeoxyglucose (FDG) uptake in both RVH and LVH. [13],[14] Our unpublished data show that O 2 consumption decreases in RVH, which we believe is related to reduced glucose oxidation.
Another factor that may impede RV function in RVH is activation of HIF-1α [Figure 1]. This leads to increased RV endothelin expression, which may deteriorate RV function and further promote glycolysis. [15] Since HIF-1α regulates numerous metabolic responses to ischemia and hypoxia, such as activation of glycolysis, it is likely to be involved in RVH-related metabolic changes. [16] PDK is another key regulator of glucose oxidation, which is dysregulated in RVH [Figure 1]. Activated PDK inhibits pyruvate dehydrogenase (PDH), thereby blocking Krebs' cycle. [17] Sharma et al., have noted that in contrast to the normal RV, which can vary its substrate utilization from fatty acids to glucose as needed, RVH is associated with a persistent reliance on glucose metabolism. [18] In hypoxia-induced RVH, they noted that expression of the GLUT4 significantly increases only in the RV (not the LV), whereas in the same model, PDK4 expression increased in parallel in the LV and RV. This suggests that PDK expression is regulated by hypoxia, whereas Glut 4 is regulated by pressure overload/wall stress. In contrast to RVH, GLUT4 is downreglated in LVH induced by aortic banding; [19] this implies that the upregulation of GLUT4, which supplies increased glucose to maintain energetic balance, may be a unique metabolic switch in RVH. In energy-deprived cells, AMPK stimulates fatty acid metabolism and glycolysis, resulting in increased production of ATP [Figure 1]. [20] AMPK activation in LVH and RVH [12],[21] preserves ATP levels by increasing glucose transport and accelerating glycolysis via the translocation of glucose transporters to the membrane (including GLUT4) and inhibiting acetyl CoA carboxylase. [20] One of the consequences of the metabolic shift (at least in PASMC) is a decrease in the expression of certain K + channels. In chronic hypoxic PAH, AMPK activation depresses the expression of O 2 -sensitive K channel in PASMC. [22] Likewise, the activation of HIF-1a in PASMC in PAH leads to decreased expression of Kv1.5. [8] Taken together, all the evidences strongly suggest that there is depressed glucose oxidation and increased glycolysis in RVH. The activation of HIF-1a and AMPK are likely central to this metabolic shift and may also account for a downregulation of K + channels [Figure 1].| [Figure 1] |  | Figure 1: Mechanisms of impaired glucose oxidation and enhanced glycolysis in RVH. In RVH, PDK and HIF-1á are activated. Activation of HIF-1á transactivates many glycolytic genes and also inhibits oxidative metabolism by increasing PDK expression. The interaction of HIF-1á and PDK constitutes a positive feedback mechanism to inhibit PDH and mitochondria respiration. Activation of AMPK enhances activation of GLUT4 and consequently glucose uptake, thereby supporting the glycolytically dependent RV in RVH. Both AMPK and HIF-1á activation depress K+ channel activity
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Metabolically driven electrical remodeling in RVH
A clue to the cause of RV dysfunction comes from studies of pulmonary artery smooth muscle cells (PASMCs) in PAH. The PASMCs are hypertrophied and display altered metabolism (increased glycolysis and a reversible impairment in mitochondrial function). [23] PAH PASMC has a metabolically mediated downregulation of the expression of specific voltage-gated potassium channels [14] (e.g. Kv1.5 and Kv2.1). The restoration of oxidative phosphorylation using DCA restores the K + channel function and regresses hypertrophy of the PASMC. [3],[8] Preliminary data suggest that cardiomyocytes of the RV in RVH exhibit similar metabolic changes. These metabolic changes are associated with impaired RV function and delayed cardiac repolarization manifest as the prolongation of myocyte action potential duration (APD). This is likely due to ionic remodeling (loss of repolarizing K + channels). These metabolic and electrical changes within the RV cardiomyocytes constitute a potential therapeutic target in RV dysfunction.
Recent research from our laboratory reveals that the prolongation of APD evolves as RVH increases in severity [Figure 2]d and e. This appears to reflect the downregulation of repolarizing K + channels in cardiac myocytes, which is consistent with the reported downregulation of voltage-gated K + channels, such as Kv4.2 and Kv4.3, in severe RVH. [24] The clinical relevance of prolongation of APD is unknown. While PAH patients have a propensity for relatively sudden cardiac death, they are not known to have an excessive incidence of ventricle arrhythmias. Ionic remodeling in RVH may also contribute to reduced RV contractile function in PAH.| [Figure 2] |  | Figure 2: The properties of RVH induced by monocrotaline (MCT) (a) Right ventricular free wall (RVFW, <-> in green) is thickened and pulmonary acceleration time (PAAT, - in red) is shortened in the MCT group vs control (CTR) by applying Doppler echocardiography. (b) Dystrophin staining demonstrates RVH induced by MCT. (c) In a Langendorff setting, the RV systolic pressure (RVSP) signifi cantly increases the RVH. (d) Monophasic action potential (MAP) measured in a Langendorff setting is prolonged in RVH. (e) The prolongation of the duration of 90% repolarization in MAP has a linear relationship with the increase in RVSP induced by MCT
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Dichloroacetate
DCA is a prototypic inhibitor of PDK and thereby activates PDH. [25] Our previous studies showed that DCA promotes glucose oxidation in PAH. [8],[10] DCA's metabolic effects can restore normal mitochondrial function in the smooth muscle cells of Fawn Hooded rats (FHR), a unique strain that spontaneously develops lethal PAH with age. [8] By normalizing the mitochondrial generation of reactive O 2 species, DCA inactivates HIF-1a and restores Kv1.5 channel expression and lowers cytosolic calcium in FHR PASMC. [8] As a result, DCA increases functional capacity, reduces pulmonary hypertension and enhances survival in PAH without overt toxicity in rats. [3],[8] In PAH induced by chronic hypoxia, DCA significantly improved pulmonary artery pressure, reduced RVH and restored O 2 -sensitive K+ currents in pulmonary artery smooth muscle cells. [8] However, the effects of DCA on the right ventricular myocardium have not been studied. Wambolt et al., found in an LVH model where the heart was challenged with ischemia-reperfusion that DCA doubled glucose oxidation and improved LV function in both hypertrophied and control hearts DCA. [26] DCA also reverses the depressed density of I to in surviving cardiomyocytes from infarcted rat heart, [27] suggesting a link between metabolic change and K + channel expression in ventricular hypertrophy.
Significance
RV function is a major determinant of functional capacity and prognosis in PAH. We hypothesize that metabolic changes in the RV that favor glycolysis may depress RV function in part by prolonging APD. These metabolic and electrical changes can be reversed by using drugs such as dichloroacetate. Although RVH occurs in response to vascular obstruction, it may be possible to therapeutically target the RV in PAH using metabolic therapies.
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[Figure 1], [Figure 2]
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