Published online before print April 17, 2003, doi: 10.1161/01.RES.0000071749.22027.45
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© 2003 American Heart Association, Inc.
Integrative Physiology |
COX-2–Dependent Cardiac Failure in Gh/tTG Transgenic Mice
From the Center for Experimental Therapeutics (Z.Z., R.V., P.M., J.A.L., S.A., D.P., G.A.F.), University of Pennsylvania School of Medicine, Philadelphia, Pa; and the Division of Cardiovascular Medicine (M.S.S.), University of Pennsylvania School of Medicine Philadelphia, Pa.
Correspondence to Garret A. FitzGerald, MD, Center for Experimental Therapeutics, University of Pennsylvania School of Medicine, 153 Johnson Pavilion, 3620 Hamilton Walk, Philadelphia, PA 19104-6084. E-mail garret{at}spirit.gcrc.upenn.edu
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Abstract |
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Gh is a GTP binding protein that couples to the thromboxane receptor (TP), but also functions as tissue transglutaminase II (tTG). A transgenic mouse model was generated in which Gh was overexpressed (GhOE) in ventricular myocytes under the control of the
-myosin heavy chain promoter. Heart rate was elevated and both blood pressure and left ventricular ejection fraction were depressed in GhOEs. Left ventricular mass was increased, consistent with genetic and ultrastructural evidence of hypertrophy. Fibrosis and apoptosis were also augmented. Survival declined disproportionately in older GhOEs. Cardiomyocyte expression of COX-2, thromboxane synthase (TxS), and the receptors for TxA2 (the TP), PGF2 (the FP), and PGI2 (the IP) were upregulated and urinary 8,12-iso-iPF2-VI,2,3-dinor-6-keto-PGF1 and 2,3-dinor-thromboxane B2 were increased in GhOEs, reflecting increased lipid peroxidation and cyclooxygenase (COX) activation. Selective COX-2 inhibition, TP antagonism, and suppression of lipid peroxidation each rescued the cardiac phenotype. Infusion of an FP agonist exacerbated the phenotype, whereas administration of an IP agonist improved cardiac function. Directed cardiac overexpression of Gh/tTG causes both TG activation and increased TP/Gh-dependent signaling. The COX-2–dependent increase in TxA2 generation augments cardiac hypertrophy, whereas formation of PGI2 by the same isozyme ameliorates the phenotype. Oxidant stress may contribute, via regulation of COX-2 expression and/or ligation of the TP and the FP by isoprostanes. Gh/tTG activation regulates expression of COX-2 and its products may differentially modulate cardiomyocyte commitment to cell death or survival.
Key Words: cardiomyocytes • cyclooxygenase • thromboxane • tissue transglutaminase • G proteins
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Introduction |
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Tissue transglutaminase (tTG), or calcium-sensitive TG II, catalyzes polymerization reactions thought integral to stabilization of the protein scaffold in apoptotic cells, preventing leakage of destructive intracellular components into the extracellular milieu and preparing them for phagocytosis.1,2 Both colocalization of tTG expression with markers of apoptosis and the use of tTG inhibitors have supported a role for this enzyme in the apoptotic pathway.3,4 The activity of tTG has also been implicated in the fibrogenesis that accompanies apoptosis in some models.5 Although deletion of tTG permits fetal survival,6,7 it appears to modulate the apoptotic response to diverse stimuli ex vivo.7
Interestingly, tTG can also function as a GTP-binding protein, termed Gh.8 Indeed, we previously reported the cosolubilization and partial purification of the thromboxane receptor (TP) with a high molecular weight G protein (
80 kDa), characteristic of Gh, from human platelets.9 TP isoforms and Gh coimmunoprecipitate from platelets and vascular tissues and TP signals, in an isoform-dependent manner, via Gh in an expression system.10 Ligation both of the 1B and 1D adrenoreceptor isoforms and of the oxytocin receptor engages Gh and, like the TP, increases intracellular calcium and/or inositol phosphates in expression systems,11–13 apparently via phospholipase C 
1.14,15 Both GTP and GDP readily bind tTG.16 Distinct GTP binding and TG domains have been identified within Gh/tTG,17 and the latter function may be negatively regulated by GTP binding.18 Thus, whereas receptor ligation may inactivate TG function by inducing GTP binding, a subsequent increase in intracellular calcium may enhance TG activity.
The role of prostaglandins and their free radical catalyzed isomers, the isoprostanes (iPs), in the modulation of cardiac function is poorly understood. However, cyclooxygenase (COX)-2 is upregulated in animal models of cardiac failure,19,20 and its expression has been detected in cardiomyocytes in heart failure in humans.21 Deletion of the COX-2 gene may result in myocardial fibrosis.22 Interestingly, expression of COX-2 has been associated with both the initiation and prevention of apoptosis, perhaps reflective of variations in the cell-specific pattern of product formation.23,24 Cardiac failure is also associated with increased generation of iPs, which may act as incidental ligands at prostaglandin receptors.25–27 The present studies investigate the relationship between Gh/tTG and COX-2. A transgenic mouse model overexpressing Gh/tTG revealed an unexpected dependence of the cardiac phenotype on COX-2–derived thromboxane (Tx) A2, which superseded the effects of the more conventional product of this enzyme in cardiomyocytes, prostacyclin (PGI2).
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Materials and Methods |
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Generation of Transgenic Mice
Generation of transgenic mice is described in the expanded Materials and Methods in the online data supplement available at http://www.circresaha.org.
Histological, Biochemical, and Genetic Analyses
These are described in the expanded Materials and Methods (see online data supplement).
Analysis of 8,12-iso-iPF2-VI, 2,3-dinor-6-keto PGF1 and 2,3-dinor-thromboxane B2
Urine collections (24-hour) from 7- to 10-month-old mice, corresponding to the time of evaluation of cardiac function, were analyzed as previously described.28,29
Physiological Measurements
The hemodynamic and biochemical analyses are described in the expanded Materials and Methods (see online data supplement).
Statistical Analysis
Data are reported as mean±SEM (n). Statistical comparisons were performed by analysis of variance (ANOVA) and using two-tailed Student’s t test comparisons as appropriate. Values of P<0.05 were considered significant. Life table analysis was performed on the survival data.
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Results |
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Animals from line 53 expressed Gh at higher levels than animals from line 47 and were used for the majority of the experiments (Figures 1A and 1B). Similar results were obtained for Gh mRNA by Northern blotting. Analysis of protein extracted from lung, kidney, and liver revealed no difference in Gh expression between the transgenic animals and WT controls. Cardiac TGase activity was increased in a gene dose-dependent fashion in the GhOEs (online Figure 1, in the online data supplement available at http://www.circresaha.org). There was no difference in G
s, Gq, Gq/11, or Gß expression between the two transgenic lines and WT mice (data not shown), but Gi protein expression was higher in line 53 GhOEs, compared with both line 47 GhOEs and with WT mice (Figure 1C). Life table analysis revealed a delayed increase in mortality in line 53 GhOEs compared with WTs (Figure 1D). However, the difference only became pronounced in older (15 months) mice, after the emergence of the cardiac phenotype. No difference in survival was noted in line 47 GhOEs (data not shown).
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Fibrosis and Apoptosis
Staining for heart collagen was performed in 3- to 4-month and 9- to 10-month-old WT and line 53 GhOE mice. Fibrosis was not evident in any 3- to 4-month-old mice, but was increased at 9 to 10 months in the GhOEs (Figures 2A and 2B). TUNEL staining was performed in the same animals used for collagen staining. Again, no difference in the percentage of apoptotic cells was evident in 3- to 4-month-old mice. However, a higher percentage of apoptotic cells were apparent in 9- to 10-month-old GhOEs compared with their WT littermates (Figures 2C and 2D). Ultrastructural analysis of myocardium in 9- to 10-month old animals revealed myofibrillar disarray (Figure 2E) and disordered mitochondria (Figure 2F) in line 53 GhOEs. There was a gene dose dependent increase in expression of -skeletal actin, and ß myosin heavy chain, but not of ANF, in the transgenic animals (online Figure 2).
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Prostanoids
Expression of COX-2, but not COX-1 mRNA, was increased in the older GhOEs compared with WTs. Expression of TxS was also increased in GhOEs (Figures 3A and 3B). Western blotting confirmed increased expression of COX-2 and TP protein in the transgenic animals (Figure 3C). mRNA for the receptors for prostacyclin (PGI2) and PGF2, the IP and the FP, respectively, was also increased in the hearts of GhOEs (Figures 3A and 3B).
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Consistent with these observations, we found that excretion of 2,3-dinor-6-keto PGF1 (PGI-M) and 2,3-dinor thromboxane B2 (Tx-M), major urinary metabolites of PGI2 and Tx, respectively, were elevated in 7- to 10-month-old GhOEs compared with WT animals (Table 1). Finally, urinary excretion of 8,12-iso-iPF2-VI was also increased in older GhOEs.
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Physiological Studies
Analysis of variance revealed a dose response relationship (F=19.9; P<0.05) between Gh expression and cardiac function in 7- to 10-month-old mice (Table 2), but not in 3- to 4-month-old mice (data not shown). Subsequent pairwise comparison between the two transgenic lines only attained significance for left ventricular mass, in which the most marked alteration was evident. The heart weight/body weight ratio and heart rate were also increased and correspondingly, the ejection fraction and systolic blood pressure were decreased in line 53 GhOEs, when compared with WT mice (Table 2).
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We next sought to clarify the origin and functional importance of the altered prostanoid formation in the GhOEs. First, we utilized two structurally distinct COX-2 inhibitors, nimesulide29 and MF tricyclic.30 Given that COX-2 is the dominant source of PGI2 formation by cardiomyocytes in rodents31 and of PGI-M excretion in mice29 and humans,32 it was unsurprising that both of these compounds depressed PGI-M excretion in both WT mice and in GhOEs (Table 1). However, inhibition of COX-2 also depressed completely the increment in Tx-M excretion in GhOEs, suggesting that COX-2 was also the source of increased Tx biosynthesis in the transgenic animals.
The functional importance of the increment in PGI2 formation was assessed by evaluation of cardiac function in animals infused with the IP agonist, iloprost.33 Both ejection fraction and heart rate were corrected in the transgenic animals by iloprost (Table 3). Activation of the FP by contrast34 dose-dependently exacerbated the GhOE phenotype (Table 3).
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The depressed ejection fraction and reduction in SBP, together with the increases in both LVM and heart rate that were evident in the older line 53 GhOEs, were all corrected by treatment with nimesulide, a selective COX-2 inhibitor (Figure 4A). MF tricyclic, a structurally distinct COX-2 inhibitor, also rescued the cardiac phenotype in older GhOEs (Figure 4B). Nimesulide also decreased both the number of apoptotic cardiomyocytes and the degree of myocardial fibrosis in the transgenic animals (Figures 2A through 2D).
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TP expression was increased in GhOE and Gh coimmunoprecipitated from cardiac tissue of GhOEs with the TP (online Figure 3). Furthermore, there was evidence of Gh-dependent TP activation. Stimulation of cardiac tissue with a TP agonist resulted in augmented ERK activation in GhOEs and this effect was blocked by neutralization of Gh (online Figure 4). We utilized a TP antagonist, SQ 29,548,35 to examine the functional relevance of increased Tx biosynthesis in GhOEs. We confirmed that the dosing regimen of SQ 29,548 had attained TP antagonism by measurement of a rightward shift in the TP agonist–induced platelet aggregation response ex vivo (data not shown) as previously described.28 TP antagonism, like COX-2 inhibition, rescued the cardiac phenotype in older line 53 GhOE mice (Figures 5A and 5B). These mice also exhibit increased iP generation, which may activate the TP and/or the FP.25,26 Suppression of iP generation with vitamin E (Table 1) also diminished the severity of the cardiac phenotype in GhOEs (Figure 4B).
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Discussion |
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Cardiac hypertrophy and/or decompensation are phenotypic consequences of directed overexpression of several G proteins, including Gq, Gi, and Gh/tTG, in cardiomyocytes.36–39 However, the mechanisms that result in these phenotypes are poorly understood. We focused on Gh/tTG, as it has been implicated in proapoptotic pathways (1, 2, and 7). Cardiomyocyte apoptosis is a feature of many forms of heart failure.40 We were interested in the possible role of COX-2 in mediating the consequences of cardiac overexpression of Gh/tTG, given the contrasting and probably product-dependent roles reported for this enzyme in apoptosis in diverse tissues.23 Both Gh and COX-2 are expressed in cardiomyocytes of patients with heart failure,21,41,42 although the clinical importance of these observations is unknown.
We report that directed overexpression of Gh/tTG, under the control of the -MHC promoter, results in age-dependent left ventricular hypertrophy and cardiac decompensation, characterized by cardiomyocyte apoptosis and fibrosis and a delayed impact on survival. Elements of this phenotype were present in a transgenic line that modestly overexpressed Gh/tTG and more floridly in a line with more robust overexpression of the transgene (line 53). Whereas COX-1 mRNA was evident in cardiomyocytes of both the WT and GhOEs, expression of COX-2, TxS, and the TP were increased coincident with the emergence of the cardiac phenotype in the transgene. Biosynthesis of both Tx and PGI2 was increased in the GhOEs and their marked suppression by two structurally distinct selective inhibitors of COX-2—nimesulide and MF tricyclic—suggest that this isozyme is the dominant source of their formation. Rescue of the cardiac phenotype by the COX-2 inhibitors places the regulation of COX-2 downstream of Gh/tTG overexpression in cardiomyocytes and implicates a COX-2 product in the emergence of the phenotype. Agonist activation of the TP is associated with increased signaling from the TP via Gh, resulting in ERK activation. Furthermore, tTG activity is also increased. This can result in amidation of RhoA, resulting in activation of mitogen-activated protein kinases (MAPKs).43 Thus, activation of either or both of the Gh or tTG functions of the overexpressed protein may regulate COX-2 expression via recognized AP-1 motifs in its promoter.19,44,45
The TP may be ligated by the COX products, TxA2 and its PG endoperoxide precursor, PGH2. Increased Tx biosynthesis, increased Gh-dependent signaling via the TP, and the effects of the TP antagonist all implicate TxA2 as the dominant COX-2–derived mediator of the cardiac phenotype in GhOEs. Urinary excretion of an abundant iP, reflective of enhanced oxidant stress, was also increased in GhOEs. This is consistent with the finding of elevated generation of iPs in human heart failure.27,46 The iPs (and, potentially, other products of lipid peroxidation) may activate the TP.25 Such a mechanism may also have been relevant to activation of the FP.26,47 Activation of the FP by a synthetic agonist, fluprostenol,48 also exacerbates the phenotype in GhOEs. Oxidant stress may upregulate COX-2,21 acting via either of two NF-
B binding motifs in its promoter,49 independent of Gh. Suppression of iP generation by vitamin E rescues the phenotype, which is consistent with a role for oxidant stress both in induction of COX-2 and in the incidental activation of the TP. Consistent with the findings of Small et al,36 we found that tTG was activated in the GhOEs. However, whereas they found no evidence of -adrenergic receptor–dependent Gh activation, TP-dependent signaling was increased in our transgenic model.
Upregulation of the IP, by contrast with the TP, appeared to subserve a compensatory response to the decline in cardiac function in GhOEs. This latter observation might be expected. Thus, expression of cardiomyocyte COX-2 is increased when cardiac failure is induced by doxorubicin in rats,19 and COX-2–dependent PGI2 formation is cardioprotective in doxorubicin-treated rats in vivo.31 PGI2 is similarly cardioprotective in rodent models of ischemia/reperfusion50 and may, at least partly, mediate the beneficial effects of elevated expression of inducible nitric oxide synthase during the late phase of preconditioning.51 However, although PGI2 biosynthesis is increased in GhOEs, COX-2 inhibition rescued, rather than exacerbated, the cardiac phenotype. In this case, the contrasting effects of another COX-2 product apparently superseded the "cardioprotective" effects of COX-2–dependent PGI2 formation.
Overexpression of Gh/tTg also resulted in increased cardiac expression of Gi. Interestingly, Gh/tTG, like Gi, has been shown to inhibit adenylate cyclase-dependent signaling.52,53 We did not address directly the contribution of Gi to the cardiac phenotype in GhOEs. However, Redfern et al,54 using pharmacological activation of a modified opioid receptor, activated conditionally overexpressed Gi in the cardiomyocytes of 8-week-old mice. This results in a ventricular conduction delay and a rapidly lethal cardiomyopathy. Although this phenotype differs in its progress and histology from the cardiac phenotype in GhOEs, it is associated with a modest increase (1.5 fold) in expression of TP, but not in the mRNA for TxS or COX-2.54 Activated TPs may potentially have engaged Gi55 to modulate the phenotype in GhOEs. For example, TP agonists activate MAPK activity in vascular cells by coupling to Gi in a PKC-dependent manner and transactivating the epidermal growth factor receptor.56 However, Gi is thought to have marginal influence in COX-2 regulation,57 consistent with the findings of Redfern et al.54 Rescue of the GhOE phenotype by COX-2 inhibitors argues against a major contribution from Gi to the alteration in cardiac function that we observed.
In summary, directed overexpression of Gh/tTG in cardiomyocytes results in activation of tTGase, increased expression of COX-2, and resultant TxA2 formation. TP/Gh-dependent signaling is also augmented in the hearts of transgenic animals, and activation of the TP (and the FP) exacerbates the phenotype. COX-2–dependent PGI2 formation, by contrast, subserves a homeostatic function. Coincident oxidant stress contributes to the phenotype, perhaps by increasing expression of COX-2 and/or by affording incidental ligands for the TP and the FP. These results suggest that the impact of COX-2 inhibitors in patients with heart failure may be complex and vary according to the pathophysiology that underlies their clinical condition.
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Acknowledgments |
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Grants HL-61364, HL-622250, and HL-57847 from the NIH supported this work. We thank Jian Yin and Lina X. Tang for their technical assistance. Dr FitzGerald is the Robinette Foundation Professor of Cardiovascular Medicine.
Received November 19, 2002; revision received April 2, 2003; accepted April 3, 2003.
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