Published online before print December 29, 2008, doi: 10.1161/HYPERTENSIONAHA.108.118349
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Hypertension. 2009;53:243.)
© 2009 American Heart Association, Inc.
Original Articles |
Transient Receptor Potential Vanilloid Gene Deletion Exacerbates Inflammation and Atypical Cardiac Remodeling After Myocardial Infarction
From the Department of Medicine (W.H., J.R., A.R.P., L.V.T., D.H.W.), Neuroscience Program (D.H.W.), and Cell and Molecular Biology Program (D.H.W.), Michigan State University, East Lansing; and the Department of Cardiology (W.H.), Chongqing Medical University, Chongqing, China.
Correspondence to Donna H. Wang, MD, FAHA, Division of Nanomedical and Molecular Intervention, Department of Medicine, B316 Clinical Center, Michigan State University, East Lansing, MI 48824. E-mail donna.wang{at}ht.msu.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
The transient receptor potential vanilloid (TRPV1) channels expressed in sensory afferent fibers innervating the heart may be activated by protons or endovanilloids released during myocardial ischemia (MI), leading to angina. Although our previous in vitro data indicate that TRPV1 activation may preserve cardiac function after ischemia-reperfusion injury, the underlying mechanisms are largely unknown. To test the hypothesis that TRPV1 modulates inflammatory and early remodeling processes to prevent cardiac functional deterioration after myocardial infarction, TRPV1-null mutant (TRPV1–/–) and wild-type (WT) mice were subjected to left anterior descending coronary ligation or sham operation. The infarct size was greater in TRPV1–/– than in WT mice (P<0.001) 3 days after MI, and the mortality rate was higher in TRPV1–/– than in WT mice (P<0.05) 7 days after MI. The levels of plasma cardiac troponin I; cytokines, including tumor necrosis factor-
, interleukin-1β, and interleukin-6; chemokines, including monocyte chemoattractant protein-1 and macrophage inflammatory protein-2; and infiltration of inflammatory cells, including neutrophils, macrophages, and myofibroblasts; as well as collagen contents, were greater in TRPV1–/– than in WT mice (P<0.05) in the infarct area on days 3 and 7 after MI. Changes in left ventricular geometry led to increased end-systolic and -diastolic diameters and reduced contractile function in TRPV1–/– compared with WT mice. These data show that TRPV1 gene deletion results in excessive inflammation, disproportional left ventricular remodeling, and deteriorated cardiac function after MI, indicating that TRPV1 may prevent infarct expansion and cardiac injury by inhibiting inflammation and abnormal tissue remodeling.
Key Words: transient receptor potential vanilloid subtype • myocardial infarction • inflammation early remodeling • transgenic animal model
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The transient receptor potential vanilloid (TRPV1) receptor is a ligand-gated nonselective cation channel, primarily expressed in sensory nerves innervating the heart and blood vessels.1,2 TRPV1 may function as a molecular integrator of multiple chemical and physical stimuli, including protons, noxious heat, endovanilloids, and capsaicin.3,4 Myocardial ischemia causes the release of protons and bradykinin, which may activate or sensitize TRPV1 expressed in cardiac sensory nerve terminals, including unmyelinated C-fibers and thinly myelinated A
-fibers, to cause angina.5,6 Indeed, ischemic stimulation of cardiac afferent nerves has been shown to be mediated by activation of TRPV1.1 Using the isolated, perfused Langendorff heart preparation, we showed that TRPV1 protects the heart from postischemic reperfusion injury possibly via increasing substance P release from sensory nerve terminals.7 Moreover, TRPV1 contributes to the beneficial effects of preconditioning of the heart against ischemia-reperfusion injury via triggering the release of substance P and/or calcitonin gene-related peptide.8 It has been shown that patients with preinfarction angina have a better prognosis after acute infarction than those without, a phenomenon ascribed to ischemic preconditioning.9 However, it is unknown whether TRPV1, a molecular transmitter of pain, plays a protective role against myocardial infarction (MI) in vivo.
MI is accompanied by an inflammatory process, which is a prerequisite for healing and scar formation.10 The degree of the inflammatory response is also a key determinant of the host’s outcome.11 The initial healing phase of the acute MI is characterized by mononuclear and fibroblast cell infiltration in the absence of polymorphonuclear leukocytes, and the later healing and remodeling processes are intertwined.12 TRPV1 has been shown to play a protective role against endotoxin-induced inflammation and to facilitate wound healing in the cornea after injury.13,14 TRPV1-induced neuropeptide release, including calcitonin gene-related peptide and substance P, has also been shown to be involved in inflammation in a manner mediating distinct effects.15,16 However, it is unknown whether TRPV1 plays a role in the cardiac inflammatory process after MI, and, if so, how it affects cardiac healing and remodeling.
Patients with asymptomatic MI show a higher mortality than those with symptoms.17,18 Increased understanding of the role of cardiac TRPV1-positive sensory nerves in MI would help in defining whether TRPV1 merely transmits a warning sign that a more severe attack is about to happen or whether its activation protects the heart from MI injury by modulating cardiac inflammatory and healing processes. This study tests the hypothesis that TRPV1 regulates the inflammatory process and early remodeling to prevent cardiac functional deterioration after MI.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Animals and Surgical Procedures
Ten-week-old male TRPV1 knockout (TRPV1–/–) or wild-type (WT) mice (Jackson Laboratory, Bar Harbor, Maine) were subjected to either a proximally left anterior descending ligation or a sham operation. Mice were anesthetized with pentobarbital (50 mg/kg IP) and ventilated with room air using a MiniVent mouse ventilator (Hugo Sachs Elektronik). Incision was made in the fourth intercostal space to open the pericardium. MI was induced by a permanent left anterior descending ligation with a 7-0 Prolene suture (Ethicon)19 and confirmed under a dissecting microscope (Olympus SZ30) by the discoloration of the ischemic area. Sham-operated animals underwent the same procedure except for left anterior descending ligation. After surgery, mice were inspected
3 times daily to check for mortality and causes of death. 19 The surviving animals were randomly measured for cardiac function and subsequently killed on day 3 or 7 after surgery.
Risk Area and Infarct Size
Evans blue dye (1%) was perfused into the aorta and coronary arteries and stained the nonischemic area blue. Hearts were excised, sliced into 5 cross-sections below the ligature, weighed, incubated in a 1% triphenyltetrazolium chloride solution, and photographed for infarct size calculation. The total left ventricular (LV) area, risk area, and infarct area were determined using computer assisted software (National Institutes of Health Image) and multiplied by the weight of the section. Three ratios were obtained: infarct area:area at risk, infarct area/left ventricle, and area at risk/left ventricle.
Immunohistochemical Studies
The mouse hearts were dissected, fixed in 4% formaldehyde solution, and embedded in paraffin. Sections (4 to 5 µm) were stained with the following antibodies: rat antimouse neutrophil antibody (AbD Serotec) or rat antimouse macrophages antibody Mac-2 (Cedarlane). After rinsing, slides were incubated with either antineutrophil (1:75) or anti–Mac-2 (1:100) and incubated with a biotinylated rabbit antirat secondary antibody (1:100, Vector Laboratories). For the staining of myofibroblasts, slides were incubated with primary mouse antimyofibroblast mixture (primary antibody, secondary antibody, and normal mouse serum at a 1:200, 1:1000, and 1:50 dilution, respectively, Vector Laboratories), avidin alkaline phosphatase solution (KPL, Kierkegaard Perry Laboratories), and then vector fast red (substrate kit 1, Vector Laboratories). Masson’s trichrome was performed according to a standard protocol.
Quantitative Analysis
All of the quantitative analyses were performed by 2 independent investigators on blind specimens. Neutrophils, macrophages, and myofibroblasts were counted in stained sections. To determine the average cellular density (cells per millimeter squared), the stained cells in the peri-infarction zone were counted in 10 different fields of x40 objective.
Determination of Plasma Cardiac Troponin I
Before each mouse was euthanized, each was injected with heparin, and the blood was collected. The plasma concentration of cardiac troponin I (cTnI) was measured as an index of cardiac cellular damage by using the quantitative rapid assay kit (Life Diagnostics).
Determination of Tissue Cytokines and Chemokines by ELISA Assay
Protein levels of cytokines, including tumor necrosis factor (TNF)-, interleukin (IL)-6, and IL-1β, and chemokines, including monocyte chemoattractant protein-1 and macrophage inflammatory protein-2 in the myocardium, were determined using various ELISA kits (R&D Systems). Tissue samples of myocardium were homogenized in ice-cold PBS buffer containing protease inhibitor mixture (50 mg wet weight per milliliter), and total proteins were extracted using NE-PER Cytoplasmic Extraction Reagents (Pierce). Total protein concentration (picograms per milligram of total tissue protein) was determined using a Bio-Rad Protein Assay (Bio-Rad Laboratories).
Hydroxyproline Assay for Collagen Content
The collagen content of the myocardial tissue was determined by the hydroxyproline assay.20 Tissue was freeze-dried, weighed, homogenized in 0.1 mol/L of NaCl and 5 mmol/L of NaHCO3, washed 5 times with the same solution, and hydrolyzed in 0.5 mL of 6 N HCl. Samples were filtered, vacuum dried, and then dissolved in distilled water. The hydroxyproline content was determined with a colorimetric assay by the protocol described in Peng et al20 using 0.5 to 5.0 µg of hydroxyproline as a calibrated curve, and the data were expressed as micrograms of collagen per milligram of dry weight, assuming that collagen contains an average of 13.5% hydroxyproline.
Transthoracic Echocardiography
Three or 7 days after MI, the mice were reanesthetized with pentobarbital (50 mg/kg IP) and placed on a heating pad. Echocardiography was performed using a GE Vivid 7/Vingmed ultrasound machine (General Electric) with a 10-MHz transducer applied parasternally to the shaved chest wall. The following parameters were measured as indicators of function and remodeling: LV internal diameter in diastole (LVIDd), LV internal diameter in systole (LVIDs), and posterior wall thickness, and the ejection fraction was directly calculated with integrated software using the Teicholz formula derived from a fractional shortening measurement (LVIDd–LVIDs/LVIDdx100).
Statistical Analysis
All of the values were expressed as means±SEs. The differences among groups for the percentages of survival rate and the area at risk were analyzed using 1-way ANOVA, followed by Bonferroni adjustment for multiple comparison. The data from the echocardiography studies; the plasma cardiac troponin I; the levels of inflammatory cells; and cytokine, chemokine, and collagen content were analyzed by 2-way ANOVA, followed by Bonferroni adjustment for multiple comparisons. Differences were considered statistically significant at P<0.05.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Lower Survival Rate in TPRV1–/– Mice After MI
All of the sham-operated mice in both strains survived until the end of the experimental period. In contrast, as shown in Figure 1, TPRV1–/– mice had a significantly lower survival rate after MI compared with that of WT mice. The most frequent cause of death in both TRPV1–/– and WT mice was LV rupture.
|
Increased Infarct Size in TRPV1–/– Mice After MI
Figure 2 shows that left anterior descending ligation produced a larger infarct size in the LV wall in TRPV1–/– mice compared with WT mice (Figure 2A). Quantitative analyses showed that the infarct size was greater in TRPV1–/– mice compared with WT mice (Figure 2B).
|
Further Elevated Plasma Cardiac Troponin I Levels in TRPV1–/– Mice After MI
Figure 3 shows that plasma cTnI levels were increased 3 days after MI in both TRPV1–/– and WT mice, with a higher level in the former than latter. On day 7 after MI, plasma cTnI levels remained elevated in TRPV1–/– but not WT mice.
|
Augmented Inflammation Infiltration in TRPV1–/– Mice After MI
Figure 4 shows that, on day 3 after MI, both TRPV1–/– and WT mouse hearts exhibited infiltration of peri-infarct myocardium with neutrophils and showed extensive replacement of dead cardiomyocytes with granulation tissues. TRPV1–/– hearts, compared with WT hearts, showed enhanced elevation of neutrophil density in the peri-infarct myocardium on days 3 and 7 after MI. Attenuated infiltration of neutrophil on day 7 compared with day 3 after MI in both TRPV1–/– and WT hearts indicated clearance of the neutrophilic infiltrate by day 7.
|
Figure 5 shows macrophage infiltration of peri-infarct myocardium on days 3 and 7 after MI in both TRPV1–/– and WT hearts. Macrophage density in the peri-infarct myocardium 3 or 7 days after MI was increased in both TRPV1–/– and WT hearts, with the former mice having even greater elevation. In contrast to the clearance of neutrophilic infiltrate on day 7, macrophage density was higher in both strains on day 7 compared with day 3 after MI. Enhanced inflammatory cell infiltration observed on days 3 or 7 after MI in TRPV1–/– mice suggests that TRPV1 deficiency might prolong the time course of resolution of the inflammatory process in healing infarct.
|
Figure 6 shows that cardiac infarcts 3 or 7 days after MI were infiltrated with myofibroblasts and characterized with spindle-shaped -smooth muscle actin–expressing cells. TRPV1–/– hearts, compared with WT hearts, showed significantly increased myofibroblast density in the peri-infarct myocardium. Similar to changes in macrophage density, myofibroblast density was higher in both strains on day 7 compared with day 3 after MI.
|
Augmented Expression of Inflammatory Cytokines and Chemokines in TRPV1–/– Mice After MI
Figure 7 shows upregulated cytokines, including TNF-, IL-1β, and IL-6, and Figure 8 shows elevated chemokines, including monocyte chemoattractant protein-1 and macrophage inflammatory protein-2, in the infarct regions on day 3 or 7 post-MI in TRPV1–/– and WT mice. The increases in cytokines and chemokines at both time points were significantly higher in TRPV1–/– than in WT mice, with the exception of no significant difference in macrophage inflammatory protein-2 between TRPV1–/– and WT mice on day 7 post-MI (Figure 8B). Cytokine and chemokine levels were attenuated on day 7 compared with day 3 after MI in both TRPV1–/– and WT Hearts.
|
|
Enhanced Collagen Deposition in TRPV1–/– Mice After MI
Figure 9 shows that, in both strains, collagen continued to accumulate at the site of infarction from day 3 to day 7 after MI. In the infarct zone itself, the collagen deposition was not different between the 2 strains. However, conspicuously increased collagen deposition was observed in peri-infarct sites in TRPV1–/– compared with WT mice (Figure 9A). Quantitative analysis also showed increased collagen contents in the peri-infarct region in TRPV1–/– compared with WT mice (Figure 9B), and the increases were enhanced on day 7 compared with day 3 post-MI in both strains.
|
Enhanced Remodeling and Deterioration of Cardiac Function in TRPV1–/– Mice After MI
As shown in the Table, there was no significant difference in body weight or heart rate on days 3 or 7 post-MI among 4 groups. An increase in LV internal dimension and a decrease in ejection factor were evident on day 3 in both TRPV1–/– and WT MI groups compared with sham-operated animals, and they were worse in TRPV1–/– compared with WT mice in the MI groups. Enhanced thickening of posterior wall thickness in diastole/posterior wall thickness in systole and a further increase in LV internal dimension were observed in TRPV1–/– compared with WT mice 7 days after MI, suggesting of exaggerated progression of remodeling and LV dilation in TRPV1–/– MI mice. These geometric changes were accompanied by a further functional deterioration in TRPV1–/–-MI mice, as indicated by progressive decreases in the ejection factor compared with the corresponding WT MI mice on day 7.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
We demonstrate for the first time that TRPV1 deficiency results in increased mortality, aggravated inflammatory response, enhanced cardiac fibrosis, exaggerated progression of LV remodeling, and deteriorated cardiac function after acute MI. The molecular basis underlying deteriorated cardiac functional and structural changes post-MI may involve intensified inflammatory cell infiltration, cytokine/chemokine production/release, and collagen deposition in TRPV1–/– mice. A note of caution that the mechanisms involved in the post-MI inflammation and myocardial remodeling may include complex pathways other than the TRPV1-mediated process.6,9,10 The data generated from global knockout mice may need to be interpreted with caution in that compromised systemic changes may occur, which may affect the disease process or outcome.
Two essential prognostic factors that assess MI recovery deal with the infarct size and LV remodeling. We found that the increase in infarct size in TRPV1–/– mice was accompanied by a higher mortality rate because of LV ruptures and/or congestive heart failure. Cardiac rupture is an acute fatal complication in the early days after MI, which is primarily associated with matrix metalloproteinase–induced collagen degradation. 21 TRPV1 deletion may induce an earlier degradation of existing collagen, contributing to cardiac rupture. Given that collagen contents in the heart are the results of a dynamic balance between collagen synthesis and degradation,21,22 we are not certain whether increased collagen contents on days 3 and 7 after MI in TRPV1–/– mice were a compensatory response to an accelerated degradation of collagen or a direct stimulating effect on collagen synthesis.
Consistent with the increased infarct size, TRPV1–/– mice also presented a higher plasma cTnI level up to day 7 after MI, whereas it returned to the baseline in WT mice. In comparison with higher mammals, mice show a more rapid and transient response, with conversion of necrotic myocardium to granulation tissues mostly completed within a week.23,24 Our results of the plasma cTnI level in WT mice are consistent with these reports, whereas it takes more than a week after MI for the plasma cTnI level to return to normal in human.24
Enlarged infarct size induced by TRPV1 deficiency may involve several cell death pathways. It has been shown that TRPV1 activation inhibits TNF-dependent activation of nuclear factor-
B (NF-B).25 NF-B is an ubiquitously expressed dimeric transcription factor involved in a number of biological processes, including inflammation, cell adhesion, and cell survival.26 Activation of NF-B increases tissue injury after acute MI.27 One possible mechanism contributing to enlarged infarct size is that TRPV1 deletion would remove the inhibition of NF-B activation, resulting in NF-B–induced enhancement of inflammatory response and subsequent myocardial damage. Indeed, several cytokines, including TNF-, IL-1β, and IL-6, as well as chemokines, such as monocyte chemoattractant protein-1, have a B-binding domain in their promoter sites, and expression of these molecules is governed by NF-B.28
The consequences of inflammatory processes after MI can be favorable or harmful, with the former leading to healing and restoration of function and the latter leading to acute cardiac rupture or chronic cardiac dilatation because of excess necrosis and apoptosis.11 We observed remarkable neutrophil and macrophage infiltration into the peri-infarct area in TRPV1–/– and WT mice after MI. The peri-infarct area or infarct border zone is the site of interface between surviving cardiomyocytes and newly formed granulation tissues, has a unique extracellular matrix composition, and serves as a barrier for expansion of the inflammatory/fibrotic response into the noninfarct areas.29 Although TRPV1–/– mice showed no evidence of spontaneous cardiac inflammation, an intense inflammatory response in the peri-infarct area is triggered after MI in this strain.
Ablation of TRPV1 might affect neutrophil migration given that TRPV1 is expressed in human and murine neutrophils, and its activation leads to calcium influx.30,31 Alternatively, excessive production of proinflammatory cytokines/chemokines seen in TRPV1–/– mice is likely to contribute to intensified infiltration of the noninfarct area with neutrophils, macrophages, and myofibroblasts,32,33 resulting in expansion of granulation tissue formation, excessive collagen deposition, and disproportional remodeling in TRPV1–/– mice.34,35 Unsuppressed inflammatory response after granulation tissue formation and unlimited expansion of fibrosis to the noninfarct myocardium would prevent the switch from inflammatory to healing processes, leading to persistent tissue damage.29,36
It seems paradoxical that TRPV1-deficient mice displayed both excessive collagen deposition in the posterior wall and enlarged LV after MI, when considering that the scar is relatively nondistensible and resistant to deformation.37 The process of ventricular enlargement can be influenced by 3 interdependent factors, ie, infarct size, degree of healing, and ventricular wall stresses.38 Given that the infarct area was mostly in the anterior wall, the posterior wall may have compensated with increased thickness in the TRPV1–/– hearts and may contribute to the ventricular enlargement seen. Moreover, in light of the fact that the infarct region is particularly vulnerable to distorted forces, the presence of an enlarged left ventricle as early as 3 days after MI may exacerbate LV expansion, as noted by an increase in the end-systolic diameter (a powerful predictor of death).38
The extent of LV dilation after MI is an important determinant of risk for major adverse cardiovascular events, including ventricular arrhythmias, heart failure, and death.39 Patients with more extensive LV remodeling are at greater risk for cardiovascular fatalities, including sudden death attributable to ventricular arrhythmias because of slower pulse propagation velocities through myocardium partially replaced by fibrosis where anisotropic re-entry occurs.40 Furthermore, increased collagen deposition changes ventricular compliance, resulting in increased stiffness and altered LV performance, which contributes to increased incidence of congestive heart failure, aneurysm formation, and mortality.21 Thus, uncontrolled cardiac remodeling observed in TRPV1–/– mice would predict a worse prognosis after MI.
Clinical Perspectives
A higher mortality rate occurs among silent MI, particularly in aging and diabetic populations,17,18 where defects in TRPV1-positive sensory nerve function are known.41,42 In contrast, patients with preinfarction angina have a better prognosis after MI than those without, and TRPV1 has been implicated in mediating the pain sensation of angina and the beneficial effect of preconditioning because of preinfarct ischemia. However, direct evidence of TRPV1 playing a key role in inflammation and healing after MI is lacking. This study indicates that TRPV1 may play a protective role in postinfarction healing, possibly via the anti-inflammation mechanism, and may serve as a new target for improving clinical outcomes after acute MI.
|
Acknowledgments |
|---|
Sources of Funding
This work was supported in part by the National Institutes of Health (grants HL-57853, HL-73287, and DK67620).
Disclosures
None.
Received June 17, 2008; first decision July 12, 2008; accepted November 21, 2008.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Pan HL, Chen SR. Sensing tissue ischemia: another new function for capsaicin receptors? Circulation. 2004; 110: 1826–1831.
2. Szalasi A, Blumberg PM. Vanilloid (Capsaicin) receptors and mechanisms. Pharmacol Rev. 1999; 51: 159–212.
3. Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature. 1997; 389: 816–824.[CrossRef][Medline] [Order article via Infotrieve]
4. Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Petersen-Zeitz KR, Koltzenburg M, Basbaum AI, Julius D. Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science. 2000; 288: 306–313.
5. Zahner MR, Li DP, Chen SR, Pan HL. Cardiac vanilloid receptor 1-expressing afferent nerves and their role in the cardiogenic sympathetic reflex in rats. J Physiol. 2003; 551: 515–2314.
6. Bolli R, Latif A. No pain, no gain: the useful function of angina. Circulation. 2005; 112: 3541–3543.
7. Wang L, Wang DH. TRPV1 gene knockout impairs postischemic recovery in isolated perfused heart in mice. Circulation. 2005; 112: 3617–3623.
8. Zhong B, Wang DH. TRPV1 gene knockout impairs preconditioning protection against myocardial injury in isolated perfused hearts in mice. Am J Physiol Heart Circ Physiol. 2007; 293: H1791–H1798.
9. Yellon DM, Dana A. The preconditioning phenomenon: a tool for the scientist or a clinical reality? Cir Res. 2000; 87: 543–550.
10. Frangogiannis NG, Smith CW, Entman ML. The inflammatory response in myocardial infarction. Cardiovasc Res. 2002; 53: 31–47.
11. Nian M, Lee P, Khaper N, Liu P. Inflammatory cytokines and postmyocardial infarction remodeling. Circ Res. 2004; 94: 1543–1553.
12. Solomon SD, Pfeffer MA. Renin-angiotensin system and cardiac rupture after myocardial infarction. Circulation. 2002; 106: 2167–2169.
13. Clark N, Keeble J, Fernandes ES, Starr A, Liang L, Sugden D, de Winter P, Brain SD. The transient receptor potential vanilloid 1 (TRPV1) receptor protects against the onset of sepsis after endotoxin. FASEB J. 2007; 21: 3747–3755.
14. Murata Y, Masuko S. Peripheral and central distribution of TRPV1, substance P and CGRP of rat corneal neurons. Brain Res. 2006; 1085: 87–94.[Medline] [Order article via Infotrieve]
15. Levite M, Cahalon L, Hershkoviz R, Steinman L, Lider O. Neuropeptides, via specific receptors, regulate T cell adhesion to fibronectin. J Immunol. 1998; 160: 993–1000.
16. Helyes Z, Elekes K, Németh J, Pozsgai G, Sándor K, Kereskai L, Börzsei R, Pintér E, Szabó A, Szolcsányi J. Role of transient receptor potential vanilloid 1 receptors in endotoxin-induced airway inflammation in the mouse. Am J Physiol Lung Cell Mol Physiol. 2007; 292: L1173–L1181.
17. Tresch DD. Management of the older patient with acute myocardial infarction: difference in clinical presentations between older and younger patients. J Am Geriatr Soc. 1998; 46: 1157–1162.[Medline] [Order article via Infotrieve]
18. Rutter MK, Wahid ST, McComb JM, Marshall SM. Significance of silent ischemia and microalbuminuria in predicting coronary events in asymptomatic patients with type 2 diabetes. J Am Coll Cardiol. 2002; 40: 56–61.
19. Gao XM, Dart AM, Dewar E, Jennings G, Du XJ. Serial echocardiographic assessment of left ventricular dimensions and function after myocardial infarction in mice. Cardiovasc Res. 2000; 45: 330–338.
20. Peng H, Carretero OA, Alfie ME, Masura JA, Rhaleb NE. Effects of angiotensin-converting enzyme inhibitor and angiotensin type 1 receptor antagonist in deoxycorticosterone acetate-salt hypertensive mice lacking Ren-2 gene. Hypertension. 2001; 37: 974–980.
21. Sun M, Dawood F, Wen WH, Chen M, Dixon I, Kirshenbaum LA, Liu PP. Excessive tumor necrosis factor activation after infarction contributes to susceptibility of myocardial rupture and left ventricular dysfunction. Circulation. 2004; 110: 3221–3228.
22. Dewald O, Ren G, Duerr GD, Zoerlein M, Klemm C, Gersch C, Tincey S, Michael LH, Entman ML, Frangogiannis NG. Of mice and dogs: species-specific differences in the inflammatory response following myocardial infarction. Am J Pathol. 2004; 164: 665–677.
23. Virag JI, Murry CE. Myofibroblast and endothelial cell proliferation during murine myocardial infarct repair. Am J Pathol. 2003; 163: 2433–2440.
24. Cummins B, Auckland ML, Cummins P. Cardiac-specific troponin-I radioimmunoassay in the diagnosis of acute myocardial infarction. Am Heart J. 1987; 113: 1333–1344.[CrossRef][Medline] [Order article via Infotrieve]
25. Singh S, Natarajan K. Capsaicin (8-methyl-N-vanillyl-6-nonenamide) is a potent inhibitor of nuclear transcription factor-kappa B activation by diverse agents. J Immunol. 1996; 157: 4412–4420.[Abstract]
26. Baeuerle PA, Baltimore D. NF-kappa B: ten years after. Cell. 1996; 87: 13–20.[CrossRef][Medline] [Order article via Infotrieve]
27. Misra A, Haudek SB, Knuefermann P, Vallejo JG, Chen ZJ, Michael LH, Sivasubramanian N, Olson EN, Entman ML, Mann DL. Nuclear factor-kappaB protects the adult cardiac myocyte against ischemia-induced apoptosis in a murine model of acute myocardial infarction. Circulation. 2003; 108: 3075–3078.
28. Li HL, Zhuo ML, Wang D, Wang AB, Cai H, Sun LH, Yang Q, Huang Y, Wei YS, Liu PP, Liu DP, Liang CC. Targeted cardiac overexpression of A20 improves left ventricular performance and reduces compensatory hypertrophy after myocardial infarction. Circulation. 2007; 115: 1885–1894.
29. Frangogiannis NG, Ren G, Dewald O, Zymek P, Haudek S, Koerting A, Winkelmann K, Michael LH, Lawler J, Entman ML. Critical role of endogenous thrombospondin-1 in preventing expansion of healing myocardial infarcts. Circulation. 2005; 111: 2935–2942.
30. Heiner I, Eisfeld J, Lückhoff A. Role and regulation of TRP channels in neutrophil granulocytes. Cell Calcium. 2003; 33: 533–540.[CrossRef][Medline] [Order article via Infotrieve]
31. Waning J, Vriens J, Owsianik G, Stüwe L, Mally S, Fabian A, Frippiat C, Nilius B, Schwab A. A novel function of capsaicin-sensitive TRPV1 channels: involvement in cell migration. Cell Calcium. 2007; 42: 17–25.[Medline] [Order article via Infotrieve]
32. Hensellek S, Brell P, Schaible HG, Bräuer R, Segond von Banchet G. The cytokine TNFalpha increases the proportion of DRG neurones expressing the TRPV1 receptor via the TNFR1 receptor and ERK activation. Mol Cell Neurosci. 2007; 36: 381–391.[Medline] [Order article via Infotrieve]
33. Zhang N, Inan S, Cowan A, Sun R, Wang JM, Rogers TJ, Caterina M, Oppenheim JJ. A proinflammatory chemokine, CCL3, sensitizes the heat- and capsaicin-gated ion channel TRPV1. Proc Natl Acad Sci U S A. 2005; 102: 4536–4541.
34. van Amerongen MJ, Harmsen MC, van Rooijen N, Petersen AH, van Luyn MJ. Macrophage depletion impairs wound healing and increases left ventricular remodeling after myocardial injury in mice. Am J Pathol. 2007; 170: 818–829.
35. Szabó A, Czirják L, Sándor Z, Helyes Z, László T, Elekes K, Czömpöly T, Starr A, Brain S, Szolcsányi J, Pintér E. Investigation of sensory neurogenic components in a bleomycin-induced scleroderma model using transient receptor potential vanilloid 1 receptor- and calcitonin gene-related peptide-knockout mice. Arthritis Rheum. 2008; 58: 292–230.[Medline] [Order article via Infotrieve]
36. Nathan C. Points of control in inflammation. Nature. 2002; 420: 846–852.[CrossRef][Medline] [Order article via Infotrieve]
37. Parmley WW, Chuck L, Kivowitz C, Matloff JM, Swan HJ. In vitro length-tension relations of human ventricular aneurysms. Relation of stiffness to mechanical disadvantage. Am J Cardiol. 1973; 32: 889–894.[Medline] [Order article via Infotrieve]
38. Pfeffer MA, Braunwald E. Ventricular remodeling after myocardial infarction. Experimental observations and clinical implications. Circulation. 1990; 81: 1161–1172.
39. St John Sutton M, Pfeffer MA, Moye L, Plappert T, Rouleau JL, Lamas G, Rouleau J, Parker JO, Arnold MO, Sussex B, Braunwald E. Cardiovascular death and left ventricular remodeling two years after myocardial infarction: baseline predictors and impact of long-term use of captopril: information from the Survival and Ventricular Enlargement (SAVE) Trial. Circulation. 1997; 96: 3294–3299.
40. St John Sutton M, Lee D, Rouleau JL, Goldman S, Plappert T, Braunwald E, Pfeffer MA. Left ventricular remodeling and ventricular arrhythmias after myocardial infarction. Circulation. 2003; 107: 2577–2582.
41. Wang S, Davis BM, Zwick M, Waxman SG, Albers KM. Reduced thermal sensitivity and Nav1.8 and TRPV1 channel expression in sensory neurons of aged mice. Neurobiol Aging. 2006; 27: 895–903.[CrossRef][Medline] [Order article via Infotrieve]
42. Bour-Jordan, Bluestone JA. Sensory neurons link the nervous system and autoimmune diabetes. Cell. 2006; 127: 1097–1099.[Medline] [Order article via Infotrieve]
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||