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1 Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130; 2 Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107; and 3 Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas 66506
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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We investigated the effects of PR-39, a recently discovered neutrophil inhibitor, in a murine model of myocardial ischemia-reperfusion injury. Mice were given an intravenous injection of vehicle (n = 12) or PR-39 (n = 9) and subjected to 30 min of coronary artery occlusion followed by 24 h of reperfusion. In addition, the effects of PR-39 on leukocyte rolling and adhesion were studied utilizing intravital microscopy of the rat mesentery. The area-at-risk per left ventricle was similar in vehicle- and PR-39-treated mice. However, myocardial infarct per risk area was significantly (P < 0.01) reduced in PR-39 treated hearts (21.0 ± 3.8%) compared with vehicle (47.1 ± 4.8%). Histological analysis of ischemic reperfused myocardium demonstrated a significant (P < 0.01) reduction in polymorphonuclear neutrophil (PMN) accumulation in PR-39-treated hearts (n = 6, 34.3 ± 1.7 PMN/mm2) compared with vehicle-treated myocardium (n = 6, 59.7 ± 3.1 PMN/mm2). In addition, PR-39 significantly (P < 0.05) attenuated leukocyte rolling and adherence in rat inflamed mesentery. These results indicate that PR-39 inhibits leukocyte recruitment into inflamed tissue and attenuated myocardial reperfusion injury in a murine model of myocardial ischemia-reperfusion.
intravital microscopy; reactive oxygen species; myocardial injury; leukocyte accumulation
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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POLYMORPHONUCLEAR NEUTROPHIL (PMN) infiltration into the postischemic reperfused myocardium has previously (11) been implicated in the pathogenesis of ischemia-reperfusion injury. Production of reactive oxygen species and PMN degranulation, resulting in the release of proteolytic enzymes within the ischemic reperfused myocardium, may contribute to myocyte death and subsequent myocardial dysfunction (11).
Reactive oxygen species, such as superoxide radical, hydrogen peroxide, and hydroxyl radical, have been implicated in the pathogenesis of ischemia-reperfusion injury in a variety of organs, including the brain (33), large intestine (28), and heart (14). Numerous studies have quantified an increase in reactive oxygen species production following myocardial ischemia-reperfusion (9, 12, 19, 36). A potential source of these reactive oxygen species is the respiratory burst production of superoxide radicals by NADPH oxidase of activated neutrophils. Xanthine oxidase and NADH/NADPH oxidase activity within endothelial cells is an additional source of toxic oxidants (10). The highly reactive nature of reactive oxygen species can result in lethal damage to vital cell components resulting in loss of cell integrity and cellular necrosis (32). Previous studies have shown that these deleterious effects are attenuated by the administration of toxic oxidant scavengers, such as superoxide dismutase and catalase (3, 14, 34). Clearly, reactive oxygen species from one or multiple sources can contribute to the development of myocardial ischemia-reperfusion injury.
The recent isolation of a novel proline-arginine-rich antimicrobial peptide, PR-39, from pig intestine may aid in the investigation of myocardial ischemia-reperfusion injury (1). PR-39 has bactericidal properties that are unique in that it kills by a non-pore-forming mechanism that inhibits DNA and protein synthesis in gram-positive and gram-negative bacteria (5). Other effects of PR-39 include increased syndecan expression, a proteoglycan involved in wound repair (6). Additionally, this peptide has also been shown to be a powerful inhibitor of neutrophilic NADPH oxidase activity by interacting with the p47phox subunit (31). Furthermore, PR-39 has been shown to prevent neutrophil recruitment following ischemia and reperfusion possibly by downregulation of endothelial cell adhesion molecules (18). The availability of synthetic PR-39 affords the opportunity to investigate the pathophysiological role of neutrophil recruitment in the development of myocardial ischemia-reperfusion injury.
Because of the potent antineutrophil action of PR-39, we hypothesized that this novel agent might attenuate myocardial ischemia-reperfusion injury and inhibit neutrophil-endothelial adherence within the microcirculation. To test this hypothesis, mice were subjected to acute coronary artery ligation and reperfusion following pretreatment with the peptide PR-39. In additional experiments, the recruitment of leukocytes to the inflamed mesentery following PR-39 treatment was assessed using intravital microscopy in rats.
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MATERIALS AND METHODS |
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Peptide treatment. PR-39 was supplied by Dr. Chris Ross at Kansas State University College of Veterinary Medicine. The peptide was synthesized by solid-phase method, using t-butyloxycarbonyl chemistry as previously described (30) with greater than 90% purity.
Male SV129 mice, utilized for the myocardial ischemia-reperfusion protocol, were injected with the PR-39 peptide (14 mg/kg, n = 9) or saline vehicle (n = 12) intravenously through the ventral tail vein 30 min prior to the surgical protocol. Male Sprague-Dawley rats utilized for intravital microscopy were superfused 30 min prior to data collection with either vehicle (n = 7), 0.5 U/ml thrombin (n = 6), or 250 µg PR-39 + 0.5 U/ml thrombin (n = 7). All investigational procedures complied with the Guide for the Care and Use of Laboratory Animals [DHHS Publication No. (NIH) 85-23, Revised 1985, Animal Resources Program, DRR/NIH, Bethesda, MD], were approved by the Council of the American Physiology Society, and complied with state and federal regulations. In addition, all experimental procedures were approved by the Louisiana State University Health Sciences Center Animal Care and Use Committee and the Animal Care and Use Committee at Thomas Jefferson University.Myocardial Ischemia: Reperfusion surgical procedure. Mice were allowed free access to normal rodent chow, exposed to 12:12-h light-dark cycles, and housed in a climate-controlled room. The surgical protocol and infarct size determination were performed similar to methods described previously (16) with several modifications due to the longer period of reperfusion in the present study. Briefly, the mice were anesthetized with pentobarbital sodium (50 mg/kg ip) and ketamine (50 mg/kg ip). Through direct visualization, the mice were orally intubated with polyethylene (PE-90) tubing. The animals were then connected to a rodent ventilator (model 683, Harvard Apparatus). The left anterior descending coronary artery (LAD) was visualized and ligated with 7-0 silk suture (Ethicon). After 30 min of LAD occlusion, the ligature was carefully severed to allow for reperfusion. Reperfusion was visually confirmed. A small piece of 7-0 silk suture was left in the myocardium to ensure that the LAD was religated in the exact same location. The chest wall was closed with three interrupted sutures (4-0 silk), and the skin was approximated with a continuous suture (4-0 silk). The animals were given butorphanol tartrate (~0.1 mg/kg ip) for analgesia. The animals were given supplemental 100% oxygen via a nasal cone and allowed to recover in a temperature-controlled area.
At the end of 24 h of reperfusion, the mice were anesthetized with pentobarbital sodium (50 mg/kg ip) and ketamine (50 mg/kg ip), a tracheostomy was performed, and the mouse was connected to the respirator. The right common carotid artery was cannulated for Evans blue dye infusion. The LAD was religated at the same location as the previous ligation, and Evans blue (1.5 ml of a 1.0% solution) was retrogradely infused into the carotid artery catheter to delineate the ischemic from the nonischemic zones. The heart was excised and cut in 1-mm-thick cross sections. Ex vivo incubation of the heart sections in 2,3,5-triphenyltetrazolium chloride for 5 min at 37°C allowed differentiation between the viable and necrotic areas of the myocardium previously rendered ischemic. Each slice was weighed and visualized under a dissecting microscope (model SZ4045, Olympus America) equipped with a Sony charge-couple device Iris color video camera (Sony Electronics). The left ventricular (LV) area, area-at-risk (AAR), and area of infarction (INF) for each slice were then determined by computer planimetry using NIH Image (version 1.57) software. The size of the myocardial infarction was determined by the following equation: weight of infarction = (A1 × W1) + (A2 × W2) + (A3 × W3) + (A4 × W4) + (A5 × W5), where A is percent area of infarction by planimetry from subscripted numbers 1-5 representing sections, and W is the weight of the same numbered section.Myocardial histology. Routine histological staining was performed on multiple sections of midventricular cardiac sections to determine the extent of PMN infiltration within the ischemic reperfused zone. Mice were subjected to the myocardial ischemia-reperfusion protocol as described above. Midventricular tissue slices (1 mm in thickness) were prepared from hearts subjected to the myocardial ischemia-reperfusion protocol. The tissue sections were immediately fixed and stored in a 10% neutral buffered Formalin solution (Sigma Diagnostics). The tissue slices were then embedded in paraffin and cut into 10-µm sections and placed on slides. The tissue specimens were then stained with Gill no. 3 hematoxylin and eosin. The slides were then viewed microscopically, and the number of PMNs per high-power field was determined. For each of the hearts examined, the number of PMNs was counted in the ischemic reperfused zone (LV anterior wall) in six fields of three independent tissue sections by a blinded observer.
Intravital microscopy of rat mesenteric venules. Sprague-Dawley rats (200-250 g), anesthetized with pentobarbital sodium (50 mg/kg), were superfused with vehicle (n = 7), 0.5 U/ml thrombin (n = 6), or 250 µg PR-39 + 0.5 U/ml thrombin (n = 7) 30 min prior to data collection. The abdominal cavity was opened via a midline laparotomy as described earlier (29). Briefly, a loop of ileal mesentery was exteriorized through the midline incision and placed in a temperature-controlled superfusion chamber. The ileum and mesentery were superfused throughout the experiment with a modified Krebs-Henseleit solution (containing, in mM, 118 NaCl, 4.74 KCl, 2.45 CaCl2, 1.19 MgSO4, and 12.5 NaHCO3), warmed to 37°C, and bubbled with 95% N2-5% CO2. A Microphoto microscope (Nikon, Tokyo, Japan) was used to visualize the mesenteric microcirculation and mesenteric tissue as previously described (29). Red blood cell velocity was determined online using an optical Doppler velocimeter obtained from the Microcirculation Research Institute (College Station, TX). This method gives an average red blood cell velocity that can be digitally displayed on a meter and allows for calculation of shear rates. Red blood cell (rbc) velocity (V) and venular diameter (D) were used to calculate venular wall shear rate (g) employing the formula: g = 8(Vmean /D)(Vmean = Vrbc/1.6) (29).
Video recordings were made at 0, 10, 20, and 30 min after initiation of superfusion for quantification of leukocyte rolling and adherence. The number of rolling and adhered leukocytes was determined offline by playback analysis of the videotape as previously reported (29). Leukocytes were considered to be rolling if they were moving at a velocity significantly slower than that of red blood cells. Leukocyte rolling is expressed as the number of cells moving past a designated point per minute. A leukocyte was judged to be adherent if it remained stationary for more than 30 s. Adherence is expressed as the number of leukocytes adhering to the endothelium per 100 µm of vessel length.Statistical analysis. All findings were analyzed with a two-tailed unpaired t-test. All statistics were calculated with StatView 4.5 (Abacus Concepts). All values are reported as means ± SE. Statistical significance was set at P < 0.05.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Myocardial AAR and infarct size.
Similarly sized AARs were observed in both vehicle (n = 12) and PR-39 (n = 9) mice. Vehicle mice
(n = 12) displayed an AAR per LV of 56.8 ± 1.9%,
and the AAR was similar in PR-39-treated hearts (56.3 ± 2.7%).
In contrast, the INF per AAR was significantly (P < 0.01) reduced by 55% in wild-type mice treated with PR-39 (21.0 ± 3.8%) compared with vehicle (47.1 ± 4.8%) (Fig.
1). Additionally, INF per LV was
26.9 ± 3.1% in the vehicle group, and this effect was
significantly (P < 0.01) diminished with the
administration of the PR-39 peptide (12.5 ± 2.8%).
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Myocardial PMN accumulation.
Histological analysis of PMN accumulation within the ischemic
reperfused myocardium of mice subjected to 30 min of coronary artery
occlusion and 24 h of reperfusion is displayed in Fig. 2. Mice administered PR-39
(n = 6) prior to myocardial ischemia-reperfusion displayed a significant (P < 0.01) reduction of 57%
in PMN infiltration (34.3 ± 1.7 PMN/mm2) compared
with mice given a saline vehicle (n = 6, 59.7 ± 3.1 PMN/mm2).
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Intravital microscopy.
The effects of thrombin and thrombin + PR-39 administration on
leukocyte rolling are presented in Fig.
3. Treatment with thrombin significantly
(P < 0.05) increased leukocyte rolling within the rat
mesentery compared with vehicle. Thrombin-stimulated leukocyte rolling
was significantly (P < 0.05) attenuated with the
addition of PR-39 at all time points except baseline. The significance of this effect increased at the 90 and 120 min time points
(P < 0.01).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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In this study, we evaluated the effects of PR-39, an inhibitor of neutrophil recruitment as well as phagocyte NADPH oxidase, in the pathogenesis of myocardial ischemia and reperfusion injury in mice. Our results clearly indicate that PR-39 attenuated the development of myocardial infarction and diminishes neutrophil sequestration following ischemia and reperfusion. These findings suggest that neutrophil recruitment contributes to cellular necrosis following ischemia and reperfusion. PR-39 has been shown to block reactive oxygen species production in a dose-dependent manner following lung ischemia or exposure to high K+ concentrations in rats (2). Furthermore, studies employing PR-39 prior to rat superior mesenteric artery occlusion and reperfusion observed a significant decrease in neutrophil translocation, reactive oxygen species production, and mesenteric venular protein leakage (18).
In addition to blunting the development of necrosis following myocardial ischemia and reperfusion, our findings suggest that PR-39 interferes with neutrophil-endothelial interaction. We found that PR-39 treatment attenuated chemically induced neutrophil rolling and firm adhesion to the endothelium in the rat mesentery. A previous study (18) demonstrated that PR-39 abrogated neutrophil rolling and firm adherence and prevented transendothelial migration following ischemia and reperfusion of the bowel mesentery. PR-39 has also been shown to downregulate phorbol 12-myristate 13-acetate (PMA)-induced expression of intercellular adhesion molecule-1 (ICAM-1) (18). It has been suggested that PR-39 may inhibit the action of a transcription factor necessary for the expression of endothelial cell adhesion molecules (ECAM) (4). PR-39 downregulation of ECAM expression could potentially explain our observations of reduced neutrophil-endothelial interaction and attenuated PMN accumulation within the ischemic reperfused myocardium.
Previous studies (21, 32) have suggested that neutrophil recruitment and migration into the ischemic reperfused myocardium mediates the development of cellular necrosis. Neutropenic studies have demonstrated decreases in cellular necrosis following myocardial ischemia and reperfusion (7, 15, 20). Inhibition of neutrophil-endothelial adhesion, a necessary step in leukocyte sequestering, has been shown to protect in myocardial ischemia-reperfusion injury (17). Monoclonal antibody blockade of endothelial ICAM-1 (35) or its neutrophilic ligand CD11/CD18 (22), necessary for leukocyte firm adhesion, yielded decreased myocardial necrosis following ischemia and reperfusion. Studies in mice deficient in P-selectin (26), ICAM-1, and CD18 (27) have shown significant reductions in PMN accumulation and necrosis following myocardial ischemia-reperfusion. The involvement of neutrophils in the development of myocardial ischemia and reperfusion injury seems clear; however, the mechanisms by which activated, sequestered leukocytes damage tissue has yet to be elucidated.
The precise mechanism of action by which PR-39 prevents myocardial ischemia-reperfusion-induced phenomena, however, remains to be determined. In addition to its inhibitory interaction with the p47phox subunit of NADPH oxidase, PR-39 has been shown to interact with a similar domain within the integrin-mediated signaling protein, p130cas (6). This finding is important since p130 has been linked to multiple signal transduction pathways as well as cell transformation. Another relevant action of PR-39 is the upregulation of synedacan-1, a heparan sulfate proteoglycan important in wound healing (8) and inhibition of metastatic carcinoma invasion (25). Interactions with the cytoskeleton could be important in neutrophil transformation during infiltration. A recent study has shown that PR-39 inhibits motility and interacts with actin-based cytoskeletal components in human hepatocellular carcinoma cells (25). It is possible that PR-39 might inhibit endothelial cell surface expression of adhesion molecules such as P-selectin, E-selectin, and ICAM-1. Elucidation of the mechanism by which PR-39 prevents myocardial ischemia-reperfusion injury is difficult to identify because of its multiple interactions within the cell.
It is important to note the limitations of this study's findings. Myocardial ischemia-reperfusion injury is not completely PMN dependent. Factors such as direct ischemic cell death, Ca2+ overload (24), membrane swelling, edema (13), and apoptosis (23) also contribute to myocardial injury. Additionally, the mechanisms that contribute to myocardial ischemia-reperfusion injury in mice and rats may not correspond to those present in the human patient. The use of mice and rats as laboratory models to investigate myocardial ischemia-reperfusion injury in humans has previously been criticized due to differences in physiology between these species and humans. Furthermore, the effectiveness of PR-39 to attenuate myocardial ischemia-reperfusion injury has only been investigated in pretreated animals. Pretreatment is a major limitation since it is difficult to predict the clinical occurrence of myocardial ischemia-reperfusion. The effects of the peptide may differ significantly when administered at or following reperfusion.
In conclusion, we found that administration of PR-39 significantly reduced myocardial infarction following ischemia and reperfusion. Furthermore, treatment with PR-39 inhibited neutrophil interaction with the endothelium, resulting in reduced PMN accumulation within the myocardium.
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ACKNOWLEDGEMENTS |
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We acknowledge the Willis-Knighton Medical Center (Shreveport, LA), DeRoyal Surgical (Powell, TN), and Ethicon Surgical (Somerville, NJ) for the generous donation of surgical equipment.
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FOOTNOTES |
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This research was supported by the National Institutes of Health, Heart, Lung, and Blood Institute Grant R01-HL-60849 (to D. J. Lefer) and Program Project Grant P01-DK-43785 (to D. J. Lefer) and by American Heart Association Grant 9951428Z (to C. R. Ross).
Address for reprint requests and other correspondence: D. J. Lefer, Dept. of Molecular and Cellular Physiology, LSU Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130 (E-mail: dlefer{at}lsumc.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.
Received 30 May 2000; accepted in final form 25 July 2000.
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REFERENCES |
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RESULTS
DISCUSSION
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Q. Wang, R. V. Donthi, J. Wang, A. J. Lange, L. J. Watson, S. P. Jones, and P. N. Epstein Cardiac phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase increases glycolysis, hypertrophy, and myocyte resistance to hypoxia Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2889 - H2897. [Abstract] [Full Text] [PDF]
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 B. Grubor, D. K. Meyerholz, and M. R. Ackermann Collectins and cationic antimicrobial peptides of the respiratory epithelia. Vet. Pathol., September 1, 2006; 43(5): 595 - 612. [Abstract] [Full Text] [PDF]
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A. K. Thukkani, B. D. Martinson, C. J. Albert, G. A. Vogler, and D. A. Ford Neutrophil-mediated accumulation of 2-ClHDA during myocardial infarction: 2-ClHDA-mediated myocardial injury Am J Physiol Heart Circ Physiol, June 1, 2005; 288(6): H2955 - H2964. [Abstract] [Full Text] [PDF]
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D. Li, V. Williams, L. Liu, H. Chen, T. Sawamura, T. Antakli, and J. L. Mehta LOX-1 inhibition in myocardial ischemia-reperfusion injury: modulation of MMP-1 and inflammation Am J Physiol Heart Circ Physiol, November 1, 2002; 283(5): H1795 - H1801. [Abstract] [Full Text] [PDF]
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J. Bao, K. Sato, M. Li, Y. Gao, R. Abid, W. Aird, M. Simons, and M. J. Post PR-39 and PR-11 peptides inhibit ischemia-reperfusion injury by blocking proteasome-mediated Ikappa Balpha degradation Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2612 - H2618. [Abstract] [Full Text] [PDF]
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 S. Sanada, M. Kitakaze, K. Node, S. Takashima, A. Ogai, H. Asanuma, Y. Sakata, M. Asakura, H. Ogita, Y. Liao, et al. Differential Subcellular Actions of ACE Inhibitors and AT1 Receptor Antagonists on Cardiac Remodeling Induced by Chronic Inhibition of NO Synthesis in Rats Hypertension, September 1, 2001; 38(3): 404 - 411. [Abstract] [Full Text] [PDF]
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