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1 Cardiology Unit, Department of Medicine, 2 Department of Surgery, University of Rochester School of Medicine, Rochester, New York 14642; and 3 Cecile Cox Quillen Laboratory of Geriatrics, James H. Quillen School of Medicine, East Tennessee State University and James H. Quillen Veterans Affairs Medical Center, Johnson City, Tennessee 37614
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Heme oxygenase (HO)-1 converts
heme to bilirubin, carbon monoxide, and iron. Our prior work has
suggested a cardioprotective role for HO-1 in heart failure. To
test whether HO-1 (heat shock protein 32) prevents cardiomyocyte
apoptosis and cardiac dysfunction after
ischemia-reperfusion (I/R), we generated transgenic mice overexpressing HO-1 in the heart under the control of the 
-myosin heavy chain promoter. HO-1 transcript and protein increased markedly in
the heart only. In an isolated heart preparation, we observed an
enhanced functional recovery during reperfusion after ischemia in the transgenic hearts compared with nontransgenic controls. I/R
injury was also performed in intact animals by coronary ligation and
reperfusion to assess the protective role of HO-1 overexpression on
heart apoptosis. HO-1 overexpression reduced cardiac
apoptosis, as evidenced by fewer terminal deoxynucleodidyl
transferase-mediated dUTP nick-end labeling-positive or in situ oligo
ligation-positive myocytes, compared with nontransgenic mice. Our
results indicate that cardioselective overexpression of HO-1 exerts
a cardioprotective effect after myocardial I/R in mice, and this
effect is probably mediated via an antiapoptotic action of
HO-1.
heat shock protein 32; oxidative stress; myocardial protection; transgenic mice; coronary ligation
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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HEME OXYGENASES (HO) are the rate-limiting enzymes in the degradation of heme to carbon monoxide (CO), bilirubin, and iron, three important molecules that have attracted great interest because of their possible role in modulating physiological functions (1, 13, 22). Three HO isoforms (HO-1, -2, and -3), products of three distinct genes, have been identified so far (1, 13). HO-1, also known as heat shock protein (HSP) 32, is a stress-inducible protein shown to be associated with protection against cellular injury (2, 18, 22, 25, 38). Myocardial HO-1 has been induced by stress in various experimental models suggesting a cardioprotective role for this enzyme (6, 8, 10, 12, 24, 25, 30, 39, 40). We (14, 25) have recently reported that oxidative stress produced by pressure overload in the heart or ischemia-reperfusion (I/R) in the kidney induces HO-1 as a cytoprotective mechanism to preserve the tissues from stress. Recently, Yet et al. (39) reported that cardiac-specific expression of human HO-1 in mice protected the heart from I/R injury. It has also been reported that cardiac-specific overexpression of the antiapoptotic gene Bcl-2 is protective (4) and the proapoptotic gene caspase-3 is shown to be detrimental (7) to the heart from I/R injury. Because oxidative stress plays a pivotal part in the progression of cardiomyocyte damage during I/R (15, 34, 36), we therefore extended our previous observations of induction of HO-1 during oxidative stress to study the protection afforded by myocardial HO-1 in oxidative stress-induced apoptosis. We have generated cardiac-specific, overexpressing rat HO-1 transgenic (TG) mice and used these animals to investigate the role of HO-1 in protecting the cardiomyocytes from apoptosis caused by I/R.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Generation of TG Mice
We have generated a transgenic construct (Fig. 1A) containing a 918-bp rat HO-1 cDNA followed by a 600-bp fragment of human growth hormone poly(A) sequence under the control of the 5.5-kb cardiac-specific mouse-myosin heavy chain (-MHC) promoter (33), kindly
provided by Jeffrey Robins (Children's Hospital Medical Center,
Cincinnati, OH). An isolated and purified 6,418-bp fragment, after NotI digestion, was injected into the pronuclei of
fertilized C57BL/6J mouse eggs (University of Rochester, Core
Transgenic Mouse Facility). TG mice harboring the -MHC promoter/HO-1
cDNA were identified by dot-blot and Southern blot analysis of genomic DNA isolated from tail biopsies by using a 650-bp fragment of HO-1
cDNA. Mice were used at 8-12 wk of age. Animal protocols were
approved by the University Committee on Animal Resources of the
University of Rochester.
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To determine the expression of genes in the various tissues, we prepared various probes for Northern blot analysis. A HO-1 cDNA corresponding to HO-1 nucleotides +71 to +834 reported by Shibahara et al. (31) was generated by RT-PCR from total rat poly(A)+ RNA and cloned into pCRII vector. We also used, in some experiments, full-length rat HO-1 cDNA, kindly provided by Shigeki Shibahara (Tohoku University School of Medicine, Japan). A 536-bp HO-2 cDNA generated with RT-PCR based on reported sequences (28) was cloned into thyminidine deoxyadenosine (TA) cloning vector and used for probing the Northern blots. A full-length human GAPDH cDNA was kindly provided by Joseph V. Bonventre (Massachusetts General Hospital, Charlestown, MA). All of the probes were labeled with [32P]dCTP by random primers using a DNA-labeling kit (GIBCO-BRL) according to the manufacturer's instructions.
Total RNA was prepared from the mouse heart, kidney, and liver by using
TRIzol reagent per the manufacturer's instructions. Poly(A)+ RNA was isolated from total RNA by oligo(dT)
cellulose chromatography, which was formaldehyde denatured and
fractionated on 1.2% agarose gel and subsequently transferred to a
Nytran membrane by using the S&S downward transfer system (25,
26). Prehybridization and hybridization of the membranes with
appropriate 32P-labeled cDNA were performed with QuikHyb
solution (Stratagene, La Jolla, CA) as recommended. After they were
probed, membranes were washed twice for 15 min with 2× saline sodium
citrate (SSC) containing 0.1% SDS at 48°C and then washed twice with
0.2× SSC containing 0.1% SDS for 15 min. Membranes were exposed to
Kodak X-OMAT film at 
70°C with intensifying screen. The
autoradiographs were quantified with a Bio-Rad image analyzer. The
densitometric values were subsequently normalized to that of the
housekeeping gene, GAPDH, for determining the folds of induction
between experimental groups. A value of one was assigned to the value
obtained with sham-operated control animals.
For the Western blot analysis, cytosol and microsomes from the heart, kidney, and liver were prepared as detailed earlier (25, 26) and were fractionated by SDS-PAGE. Protein bands were transferred to a nitrocellulose membrane by using a Bio-Rad mini protean II transblotter unit. Western blot analysis was carried out essentially as detailed earlier (25, 26) by using commercially available anti-rat HO-1, HO-2 polyclonal, and anti-HSP90 monoclonal antibodies (StressGen Biotechnologies, Victoria, BC, Canada). The antigen-antibody complexes were visualized by chemiluminescence by using a phototope-horseradish peroxidase Western blot detection kit (New England Bio-Labs, Beverley, MA).
Hearts were also prepared for histoimmunochemistry by flushing via the aorta with PBS and then fixing in 4% formalin and embedding in paraffin. Paraffin-embedded myocardial sections (5 µm) were mounted on superfrost slides and dried at 37°C overnight. Slides were processed, and HO-1 immunostaining was carried out by using rat anti-HO-1 antibodies (1:200, StressGen) detailed by us (27). Antigen-antibody complexes were detected by Histostain-SP (Zymed Laboratories, San Francisco, CA).
Experimental Protocols
Two different experimental protocols were employed to study the functional importance of the HO-1 system in cardioprotection against I/R injury. An isolated heart Langendorff preparation was used to study the protective effect of HO-1 on cardiac contractile function against I/R injury. Intact animals were used to assess the protective effect of HO-1 overexpression on myocyte apoptosis after coronary occlusion and reperfusion.Global ischemia in vitro.
C57BL/6J non-TG and HO-1 TG littermates weighing 25-30 g were
injected with heparin sodium (500 U/kg body wt ip) 30 min before anesthetization with pentobarbital sodium (120 mg/kg ip). Hearts were
rapidly excised and perfused retrogradely at 60 mmHg by the Langendorff
technique with Krebs-Henseleit bicarbonate buffer containing (in mM)
118 NaCl, 25 NaHCO3, 4.7 KCl, 1.2 KH2PO4, 1.2 MgSO4, 1.25 CaCl2, and 11 glucose (5). After 15 min of
preliminary perfusion, a fluid-filled compliant balloon, attached to
the proximal end of a cannula, was introduced into the left ventricle
through the mitral valve. The distal end of the cannula was connected to a pressure transducer to monitor left ventricular (LV) developed pressure (LVDP), its first derivatives of maximal rate of pressure over time (dP/dt and dP/dt), and heart
rate (HR), all done with a computerized data acquisition system (DATAQ
Instruments). The balloon was initially inflated to an end-diastolic
pressure of 3-5 mmHg with 5 µl of saline, and all
subsequent measurements of LV pressures were made at this same
end-diastolic volume (5). After a 30-min stabilization
period, LV end-diastolic pressure, developed pressure,
dP/dt, HR, and coronary flow rate were recorded as baseline
control. Myocardial ischemia was then created by stopping the
aortic perfusion. After 40 min of ischemia at 37°C, hearts were reperfused for 45 min, and the hemodynamic parameters were reassessed. Cardiac injury was measured by the release of lactate dehydrogenase (LDH) in the coronary effluent, which was collected during preischemic perfusion and every 15 min during
postischemic reperfusion. Coronary flow rate was determined by
the amount of effluent collected in a specific time period. LDH
activity was determined by a CytoTox 96 assay (Promega, Madison, WI).
Regional ischemia in vivo. Mice weighing 25-30 g were anesthetized with chloral hydrate (360 mg/kg ip). An endotracheal tube (polyethylene-90) was inserted 5-8 mm from the larynx, and the mice were ventilated with room air (tidal volume of 0.5 ml/stroke) by using a rodent respirator (Columbus Instruments, Columbus, OH) set at 110-120 strokes/min. Left anterior descending (LAD) coronary artery ligation was performed as described previously (4, 5). After 30 min of ischemia, the ligation was released, and the heart was reperfused for 3 h. Mice were then euthanized with pentobarbital sodium (120 mg/kg ip), and the hearts were isolated and perfused as a Langendorff preparation for 5 min.
To measure myocyte apoptosis, a 2-mm section of the heart near the middle part of the area at risk was sliced, fixed in 4% formalin solution, and embedded in paraffin. Myocardial sections (5 µm) were mounted on superfrost slides and dried at 37°C overnight. Immunohistochemical procedures for detecting apoptotic cardiomyocytes were performed by using the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) technique with Cardio-TACS (Trevigen; Gaithersburg, MD), according to the manufacturer's instructions. In this procedure, nuclei undergoing apoptosis were stained blue (TUNEL positive). Nuclear fast red was used as a counterstain (Trevigen). TUNEL-positive myocytes were determined by randomly counting 500 cells in 10 fields (×100). The index of apoptosis was calculated as the number of apoptotic myocytes/total number of myocytes × 100. To verify that the apoptosis occurred in the myocytes, immunochemical staining of-sarcomeric actin was carried out with a -sarcomeric actin
monoclonal antibody (1:100 dilutions; Sigma, St. Louis, MO) at 4°C
overnight. Hematoxylin was used as a counterstain.
Because TUNEL assay cannot differentiate between apoptosis and
nonspecific DNA fragmentation due to necrosis, a more specific in situ
oligo ligation (ISOL) assay for identification of apoptotic nuclei
using hairpin oligonucleotide probes was performed (9). ISOL analysis was carried out in the serial section of each specimen by
the ApopTag ISOL kit by using oligo A according to the manufacturer's instructions (Intergen, Purchase, NY) with some modifications. The
endogenous biotin was blocked with an Avidin/Biotin blocking kit
(BioGenex). TACS blue label was used as a peroxidase substrate and
nuclear fast red was used as a counterstain. Oligo A was synthesized as
a modification of the method described by Didenko et al.
(9) in which the sequence of the ten 3' and ten 5' bases
were complementary and in which a biotin was attached through a
triethylene glycol linker inserted between the 13th and 14th bases.
Statistical Analysis
Results are expressed as means ± SE. Between-group comparisons were performed by using Student's t-test. A value of P < 0.05 was considered statistically significant.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Characterization of HO-1 TG Mice
We generated a line of TG mice that carried a rat HO-1 TG under the control of a mouse-MHC promoter. All HO-1 TG mice were healthy
and showed no apparent phenotypic abnormality. In addition, there was
no difference in body weight (27.8 ± 0.3 g in non-TG vs.
27.4 ± 0.7 g in HO-1 TG) or heart weight (133 ± 6 mg
in non-TG vs. 129 ± 4 mg in HO-1 TG) between age-matched HO-1 TG
(n = 14) and non-TG animals (n = 14).
The founder mouse was ~16 mo old and still alive.
We performed a detailed expression study with the offspring of the
founder mouse HO-1 TG no. 12. HO-1 transcript (1.8 kb) was detected by
using rat HO-1 full-length cDNA radioactive labeled probe. As shown in
Fig. 1B, HO-1 was predominantly expressed in the heart of
the HO-1 TG mouse compared with the kidney and liver of the same animal
or the heart, kidney, and liver of the non-TG mouse. Western blot
analysis (Fig. 1C) of tissue homogenates showed that the
HO-1 protein (32 kD) was highly expressed in the hearts of the HO-1 TG
mouse confirming the translation of the HO-1 TG, HO-1 mRNA.
Overexpression of HO-1 in the heart did not alter the expression of
other HO isoforms, such as HO-2 (Fig. 2).
The cardiac-selective overexpression of HO-1 was further corroborated
by the presence of strong immunoreactive HO-1 in the myocytes of TG
animals (Fig. 3).
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Langendorff-Perfused Hearts
We compared the cardiac parameters of HO-1 TG mouse hearts with those of their normal littermates. After 30 min of equilibration perfusion, the cardiac basal parameters were compared (Table 1). Maximum rates of pressure development during both contraction and relaxation (±dP/dt) were essentially the same in the two groups. LVDPs were 80 ± 7 mmHg in non-TG mice and 79 ± 9 mmHg in HO-1 TG mice. Heart rates and coronary flow rates were similar in both groups.
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I/R caused a 55-60% reduction of the mechanical function (LV
dP/dt, LVDP, and LVDP × HR) of
Langendorff-perfused non-TG hearts (Fig.
4). In comparison, HO-1 TG hearts had
22-26% higher recovery in these parameters (P < 0.05 vs. non-TG hearts). HR recovered completely after reperfusion and
coronary flow rate increased slightly above the baseline value, due to
postischemic coronary vasodilation. No difference was observed
in HR and coronary flow rate between the two groups.
Preischemic end-diastolic pressures of non-TG and HO-1 TG
hearts were comparable. At the end of 45-min postischemic
reperfusion, end-diastolic pressure increased to 71 ± 9 mmHg in
non-TG hearts (Fig. 5). HO-1 TG hearts
showed a significantly less elevation in end-diastolic pressure to
32 ± 6 mmHg (P < 0.05 vs. non-TG).
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Figure 6 shows the post-I/R LDH release
in non-TG and HO-1 TG hearts. LDH release did not differ significantly
between the two groups during the first 15 min of reperfusion but was
reduced markedly in TG hearts during the following 30 min of
reperfusion. Total amount of post-I/R LDH release in the non-TG group
(904 ± 179 mU/mg protein) was 3.4-fold higher than that in the
HO-1 TG group (263 ± 50 mU/mg protein, P < 0.05).
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Coronary Artery Occlusion and Reperfusion in Intact Animals
Hearts from sham-operated non-TG and HO-1 TG mice exhibited low levels of staining for TUNEL (1.7 ± 0.2 and 1.4 ± 0.1%, respectively). After I/R, the number of TUNEL-positive myocytes was increased to 22.0 ± 1.3% in the non-TG mice, but was only 7.0 ± 0.3% in the HO-1 TG heart (Fig. 7A). TUNEL-positive cells were immunoreactive to-sarcomeric actin antibodies, indicating they were
myocytes (data not shown).
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Similar to the TUNEL assay, we found a low level of ISOL-positive nuclei in myocytes of sham-operated non-TG (0.8 ± 0.1%) and HO-1 TG mice (0.9 ± 0.1%). In contrast, ISOL-positive myocyte nuclei increased significantly after I/R injury in non-TG mice (19 ± 1%) and HO-1 TG mice (5.0 ± 0.3%). The difference between the two groups was statistically significant (Fig. 7B).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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In mammalian cells, a variety of stress inducers, such as heavy metals, hyperthermia, oxidized lipoproteins, ultraviolet and visible light, inflammatory cytokines, hypoxia, and hyperoxia cause rapid and robust upregulation of HO-1 activity. Numerous reports support the hypothesis that HO-1 induction plays an important role in the cellular protection against injuries caused by oxidative stress. Our previous study (25) showed that HO-1 was specifically induced in the right ventricle of right heart failure dogs compared with that of controls, whereas there was no increase in HO-1 levels in the LV of both control and heart failure groups. We hypothesized that this differential regulation and induction of the HO-1 gene in the failing ventricle might be one of the defense mechanisms by which the heart attempts to protect itself from stress caused by congestive heart failure. In this study, we report that cardiac-specific overexpression of rat HO-1 resulted in the protection of the heart of HO-1 TG mice from I/R injury compared with that of controls in Langendorff perfusion in vitro. During the course of our studies, Yet et al. (39) reported that cardiac-specific expression of human HO-1 in mice protected the heart from I/R injury. Thus our studies further corroborate the cardioprotective effect of cardiac-specific expression of HO-1 gene during I/R in vitro and in vivo. In our studies, we have characterized the overexpression of HO-1 in the TG mice at molecular and functional levels. Most importantly, we report an antiapoptotic activity of HO-1 in protecting the cardiomyocytes from I/R-induced apoptosis in vivo in this study (Fig. 7)
It has been reported previously that upregulation of endogenous HO-1 by hemin ameliorates postischemic myocardial dysfunction in vitro (6) and decreases the infarct area in vivo (10). Recent studies (40) with partial targeted disruption of the HO-1 gene increased the susceptibility of ex vivo mouse hearts to I/R injury. In the present study, our results clearly suggest that the specific overexpression of HO-1 in the cardiomyocytes was sufficient to protect against I/R-induced apoptosis. HO-1 overexpression did not affect other genes, such as HO-2 (Fig. 3), as well as HSP90 (data not shown). This might be at least one of the ways by which HO-1 imparts its cytoprotective effects.
The mechanisms by which HO-1 exerts its antiapoptotic effect are not known. One plausible mechanism for the HO-1-imparted cardioprotection could be via bilirubin. Bilirubin has been shown to protect cardiomyocytes against oxidative damage (37) and improve postischemic cardiac function in vitro. High serum bilirubin levels are associated with decreases in risk for early familial coronary artery disease (11). Another byproduct of the HO-1 enzymatic reaction is CO, which has been shown to have potent cytoprotective effects (23). CO is involved in the vasorelaxation and suppression of platelet aggregation mediated via the activation of guanylyl cyclase and subsequent generation of cGMP (16, 17, 21, 35). CO also has been shown to protect the endothelial cells from apoptosis as well as to protect the heart after heterotrophic cardiac transplantation (3, 29, 32). HO-1 overexpression may also affect the regulation of apoptotic pathway gene(s) like Bcl2, Bax, or caspases. Apoptosis was reported in myocytes of heart failure patients (19) and an increase in the release of cytochrome c and activation of caspase-3 was also observed due to heart failure compared with normal patients (20). Cardiac-specific overexpression of Bcl-2 protected the heart from I/R-induced apoptosis (4) and overexpression of proapoptotic gene caspase-3 rendered the hearts vulnerable to I/R injury (7). We have observed that caspase-3 is downregulated in HO-1 TG mice subjected to oxidative stress by lipopolysaccharide compared with that of non-TG mice subjected to the same stress (S. R. Vulapalli and C.-S. Liang, unpublished data). In these experiments, we have not observed any difference in the basal caspase-3 activities between HO-1 TG mice and wild-type littermates. Active investigations are now in progress to further delineate the function of HO-1 in the regulation of the antiapoptotic pathway genes. The studies may lead to novel strategies that will help in preventing I/R-induced cardiac apoptosis.
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ACKNOWLEDGEMENTS |
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We thank Dr. Bill James (Intergen) for providing the ApopTag in situ oligo ligation kit. The authors thank Janice Gerloff for assistance in transgenic animal maintenance and Mary Braswell, Lou Ellen Miller, and Cathy Lande for expert technical assistance.
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FOOTNOTES |
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The study was supported, in part, by American Heart Association, New York State Affiliate and Rochester Eye and Human Parts grants (to S. R. Vulapalli), by National Heart, Lung, and Blood Institute Grant HL-68151 (to C.-S. Liang), and the Department of Veterans Affairs Medical Research Fund and American Heart Association grants (to B. H. L. Chua).
Address for reprint requests and other correspondence: S. R. Vulapalli, Cardiology Unit, Box 679, University of Rochester School of Medicine, 601 Elmwood Ave., Rochester, NY 14642 (E-mail: raju_vulapalli{at}urmc.rochester.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajpheart.00133.2002
Received 21 February 2002; accepted in final form 25 April 2002.
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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P < 0.05 compared with HO-1 non-TG postischemic LVEDP.
