Published online before print April 7, 2005
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* Immunopathology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, and
Howard Hughes Medical Institute–National Institutes of Health Research Scholar, Bethesda, Maryland
1 Correspondence: Immunopathology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Building 30, Room 325, Bethesda, MD 20892-4352. E-mail: lwahl{at}dir.nidcr.nih.gov
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(TNF-) and granulocyte macrophage-colony stimulating factor (GM-CSF) release Ang II, which is an integral component of the signal transduction pathway that leads to MMP-1 production. An Ang II-mediated increase in MMP-1 synthesis occurred only in conjunction with cytokine stimulation. Moreover, Ang II mediated its effect through the Ang II type 2 (AT2) receptor, as demonstrated by enhancement of MMP-1 production by an AT2 agonist, CGP-42112A, and inhibition of MMP-1 production by PD1233319, an AT2 antagonist. Additionally, exogenous Ang II caused a significant enhancement in MMP-1 production by cytokine-stimulated monocytes, and the most effective enhancement occurrred when Ang II was added 6 h after stimulation. Furthermore, Ang II and the AT2 agonist increased prostaglandin E2 (PGE2), which in turn mediated the increase in MMP-1, as shown by the inhibition of MMP-1 by indomethacin or aspirin. In contrast, the AT2 antagonist inhibited the PGE2 production induced by TNF- and GM-CSF. Ang II, through its interaction with the AT2 receptor, has a central role in mediating the PGE2-dependent production of MMP-1 by monocytes stimulated with TNF- and GM-CSF. These observations provide insight into the association between hypertension and acute coronary syndrome and a possible mechanism by which Ang-converting enzyme inhibitor and aspirin may reduce the risk for heart attacks.
Key Words: angiotensin II receptor subtype 2 • inflammation • cytokines
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Systemic Ang II is produced by conversion of angiotensinogen (AGT) derived from the liver to Ang I by renin from the kidney and subsequent conversion of Ang I to Ang II by ACE from the endothelial cells in the pulmonary vasculature. In addition, Ang II is produced by all of the cellular components of the vascular wall [3 , 4 ]. Monocytes/macrophages, one of the cell types in the vascular wall, has all of the components of the renin-Ang system to produce Ang II [5 , 6 ]. Moreover, these cells play a major role in development of atherosclerosis and rupture of atherosclerotic plaques [7 ]. Ang II has been colocalized to intimal macrophages in atherosclerotic lesions in human coronary atherectomy samples [8 ]. Furthermore, Ang II regulates monocyte/macrophage functions that may contribute to the pathogenesis of atherosclerosis, including increased migration [9 ] and uptake of oxidized low-density lipoprotein (LDL) [10 ].
Previous studies have shown that matrix metalloproteinases (MMPs) produced by monocyte/macrophages and other cells may cause the rupture of vulnerable plaques [7
, 11
]. Atherosclerosis is considered to be an inflammatory disease in which cytokines may play a major role in the regulation of cellular responses [7
]. Cytokines, such as tumor necrosis factor (TNF-) and granulocyte macrophage-colony stimulating factor (GM-CSF), which modulate monocyte function, have been found in the atherosclerotic plaque [12
13
14
]. Moreover, TNF- and GM-CSF in combination have been shown to stimulate the production of MMP-1, an interstitial collagenase that can cleave fibrillar collagens (types I, II, and III), by monocytes; whereas, each cytokine alone does not induce the production of MMP-1 [15
]. We have also shown that interferon-
, another cytokine found in atherosclerotic plaques [13
, 14
], in combination with GM-CSF will stimulate the production of TNF-, resulting in the induction of MMP-1 synthesis by monocytes [16
]. Additionally, the induction of monocyte MMP-1 by TNF- and GM-CSF can be enhanced by other factors, such as Chlamydia pneumoniae [17
], which has been found in the atheroma [18
19
20
]. MMP-1 has been localized in atherosclerotic plaques [21
] and is capable of degrading the extracellular matrix (ECM) in the thin fibrous cap of a vulnerable plaque that may lead to the rupture of the atherosclerotic plaque. In this study, we demonstrate that Ang II plays a major role in the enhancement of MMP-1 production by TNF-- and GM-CSF-stimulated monocytes mediated through the Ang II type 2 (AT2) receptor and prostaglandin E2 (PGE2).
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and GM-CSF (PeproTech, Rocky Hill, NJ). Other reagents added to some of the monocyte cultures were AGT, Ang I, Ang II, CGP-42112A, PD123319, aspirin, indomethacin, PGE2 (Sigma Chemical Co., St. Louis, MO), and [Sar1, Ala8]-Ang II (Calbiochem, La Jolla, CA).
Assays for MMP-1, Ang II, and PGE2
Proteins in the 48-h conditioned medium were analyzed by Western blot for MMP-1 with peptide-specific antibodies (generously provided by Dr. Henning Birkedal-Hansen, National Institute of Dental and Craniofacial Research, NIH), as described previously [15
]. Conditioned media were analyzed for Ang II production by enzyme-linked immunosorbent assay (ELISA; Cayman Chemicals, Ann Arbor, MI, or Peninsula Laboratories, San Carlos, CA) and for PGE2 production by ELISA (Cayman Chemicals), according to suggestions of the manufacturer. All experiments were repeated at least three times.
The levels of transcript of MMP-1 and ß-actin were determined using semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR). Briefly, after 12 h of incubation, mRNA was extracted from monocytes using Trizol (Gibco-BRL/Invitrogen, Gaithersburg, MD), and then MMP-1 mRNA was determined using a semiquantitative OneStep RT-PCR kit (Qiagen Inc., Valencia, CA) with ß-actin as an internal control. The primer sequences for MMP-1 were 5'-ATG CGC ACA AAT CCC TTC TAC C-3' and 5'-TTT CCT CAG AGA AAA GAG CAT CG-3'. The primer sequences for ß-actin were 5'-GAC CCA GAT CAT GTT TGA GAC CTT-3' and 5'-CTA AGT CAT AGT CCG CCC TAG AAG CAT-3'. For each reaction, 10.6 µl RNase-free water, 5 µl OneStep buffer, 10 mM deoxy-unspecified nucleoside 5'-triphosphate, 10 µM each of the primers, 1.4 ng RNA template, and 1 µl OneStep RT-PCR enzyme mix were added for a total of 25 µl. The thermocycler conditions were 30 min at 50°C for RT, 15 min at 95°C for initial PCR activation, 35 cycles of 40 s at 94°C, 45 s at 56°C, and 1 min at 72°C, and finally, 10 min at 72°C for final extension. Subsequently, the products were separated on a 1.4% agarose gel. The densitometric analysis of the RT-PCR products was performed using Scion Image for Windows (Scion Corp., Frederick, MD).
Membrane protein extraction for AT1 and AT2 receptors
Membrane protein was extracted at 0 and 24 h after stimulation with TNF- and GM-CSF, as described previously [15
, 22
]. Briefly, cells were centrifuged at 2000 rpm for 10 min and resuspended in sucrose lysis buffer. After sonication, eight to 10 pulses at 70 Hz, the samples were centrifuged at 2000 rpm for 15 min to precipitate nuclei and cell debris. Then, supernatants were transferred to fresh tubes and centrifuged at 14,000 rpm for 30 min. The pelleted protein was resuspended in phosphate-buffered saline (PBS) and sonicated by four to six quick pulses at 40–50 Hz, and 100 µg protein from each sample was analyzed for Ang II AT1 and Ang II AT2 receptors by Western blot using peptide-specific antibodies (Santa Cruz Biotechnology, CA). Each band for Ang II AT1 and Ang II AT2 was 50 kDa, based on molecular weight markers.
Fluorescent microscopy
Purified monocytes were plated at 1 x 104 in 100 µl serum-free DMEM in 24-well plates containing circular coverslips and adhered for 30 min at 37°C. The cultures were rinsed twice with ice-cold PBS (BioWhittaker) and then incubated with 20 µM fluorescein-Ang II (Sigma Chemical Co.) in 1% bovine serum albumin in PBS in the absence or presence of a tenfold excess of Ang II for 1 h at 4°C. Following incubation for 5 min at 37°C, the cells were fixed in 2% paraformaldehyde in PBS for 1 h at room temperature, mounted on Micro Slide with Fluoromount G (Surgipath Medical Industries Inc., Richmond, IL), and visualized under a fluorescent microscope.
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- and GM-CSF-stimulated monocytes plus GM-CSF, known stimulators of monocyte MMP-1 [15
]. In the absence of TNF- and GM-CSF stimulation, the media from monocyte cultures contained no detectable Ang II (Fig. 1A
). However, addition of TNF- and GM-CSF to the monocytes resulted in a release of detectable Ang II (5 ng/ml or 
10 nM) in the supernatant within 5 min, followed by a rapid disappearance of Ang II to undetectable levels by 6 h (Fig. 1A)
.
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Figure 1. Production of Ang II by monocytes and the role of Ang II and its precursors in the regulation of monocyte MMP-1 production. Purified primary human monocytes (5x106 cells/ml DMEM) were cultured in 12-well culture plates in the presence or absence of TNF- plus GM-CSF (50 ng/ml). The levels of Ang II were determined by ELISA and MMP-1 by Western blot of the 48-h conditioned media. The reagents added to the cultures remained in the culture media for the duration of the experiment. (A) Amount of Ang II present in the media at different time-points after stimulation with TNF- and GM-CSF. (B) AGT (10 nM) was added to the cultures in the presence or absence of indomethacin (10–6 M) and PGE2 (10–7 M). (C) Ang I was added to monocyte cultures at the indicated concentrations. (D) Ang II was added to monocyte cultures at the indicated concentrations.
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- and GM-CSF-stimulated monocyte production of MMP-1- plus GM-CSF-stimulated monocytes caused a marked increase in MMP-1, whereas AGT alone did not induce MMP-1 production (Fig. 1B)
. Our previous studies have demonstrated that the induction of MMP-1 occurs, in part, through a PGE2-dependent pathway. This was also the case for the increase in MMP-1 mediated by AGT, as shown by the ability of indomethacin to suppress MMP-1 production and the reversal of this inhibition by PGE2.
Next, Ang I, the precursor to Ang II, was added to human monocytes to determine its role in MMP-1 production. Similar to AGT, Ang I alone did not induce MMP-1 production (data not shown). However, in the presence of TNF- and GM-CSF, Ang I, at concentrations of 1 µM, caused a marked increase in MMP-1 production compared with controls (Fig. 1C)
. These findings suggested that AGT and Ang I, which are inactive, were converted to biologically active Ang II by monocytes, resulting in the stimulation of MMP-1 production.
Ang II was then added to monocytes to demonstrate the direct effect of this metabolite on monocyte MMP-1 production. Addition of Ang II in the absence of TNF- and GM-CSF, similar to its precursors, failed to induce MMP-1 production (data not shown). However, when Ang II was added to monocytes along with TNF- and GM-CSF, there was substantial increase in MMP-1 production compared with cytokines alone (Fig. 1D)
.
Ang II clearance by monocytes
As previously shown in Figure 1A
, Ang II produced by monocytes is cleared rapidly. To determine the amount of time it takes for Ang II to be taken up by monocytes, various concentrations of Ang II were added to monocytes along with TNF- and GM-CSF. ELISA analysis of supernatants showed that the addition of exogenous Ang II at 1 µM and lower concentrations were rapidly taken up with 10% of original concentration of exogenous Ang II remaining in the media after 4 h (Fig. 2A
). However, when 100 µM Ang II was added to the cultures, a high level of Ang II was maintained for at least 12 h (Fig. 2A)
. To further assess the endogenous levels of Ang II and clearance by monocytes [Sar1, Ala8]-Ang II [23
], a short-acting Ang receptor antagonist, which binds to AT1 and AT2 receptors, was added to monocyte cultures, thereby slowing the binding of various concentrations of Ang II. ELISA analysis showed that addition of [Sar1, Ala8]-Ang II with TNF- and GM-CSF led to a higher concentration of Ang II, which was present several hours after stimulation. The amount of Ang II present in the media following TNF- and GM-CSF stimulation was related to the concentration of [Sar1, Ala8]-Ang II, as compared with monocytes stimulated with TNF- and GM-CSF in the absence of [Sar1, Ala8]-Ang II (Fig. 2B)
.
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Figure 2. Ang II is rapidly taken up by monocytes, and the enhancement of MMP-1 synthesis is more sensitive to Ang II stimulation several hours after the addition of TNF- and GM-CSF. (A) Percentage of exogenous Ang II (0.01 µM, 1 µM, and 100 µM) remaining in the media at different time-points after the addition of Ang II to TNF-- and GM-CSF-treated monocytes. (B) Amount of Ang II in the media at different time-points after the addition of TNF- and GM-CSF alone or with the AT1 and AT2 receptor antagonist [Sar1, Ala8]-Ang II. (C) Comparison of the addition of Ang at the same time or 6 h after TNF- and GM-CSF stimulation on MMP-1 production. (D) Effect of delaying endogenous and exogenous binding of Ang II by [Sar1, Ala8]-Ang II on the MMP-1 production by cytokine-stimulated monocytes.
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and GM-CSF, we performed two experiments to determine if monocytes are more sensitive to Ang II several hours after stimulation. First, Ang II was added at 100 nM, 1 µM, and 10 µM to monocytes with TNF- and GM-CSF or 6 h after TNF- and GM-CSF stimulation. Monocytes treated with Ang II 6 h after TNF- and GM-CSF stimulation produced significantly more MMP-1 compared with controls (Fig. 2C)
. Second, analysis of MMP-1 after the addition of [Sar1, Ala8]-Ang II and cytokines showed that there was a significant increase in MMP production (Fig. 2D)
. A further increase in MMP-1 production in the presence of [Sar1, Ala8]-Ang II was detected with the addition of various concentrations of Ang II. The delay in adsorption of exogenous Ang II by [Sar1, Ala8]-Ang II resulted in a significant increase in MMP-1 at a concentration of Ang II as low as 1–100 pM (Fig. 2D)
. These findings demonstrate that monocytes are most sensitive to the enhancing effects of Ang II on MMP-1 production several hours after stimulation by TNF- and GM-CSF.
MMP-1 production by stimulated monocytes occurs through the AT2 receptor
Our study as well as others [9
, 10
] imply that there are receptors on the human monocyte surface for Ang II. We demonstrated that monocytes have Ang II receptors, and these are crucial for monocyte MMP-1 production through several experimental approaches. First, Western analysis revealed that monocytes have both types of Ang II receptors, AT1 and AT2, on the cell surface at 0 and 24 h after culture in the presence or absence of cytokines (Fig. 3A
). Second, fluorescein-labeled Ang II bound to monocytes, and this binding and uptake could be blocked by the addition of tenfold excess of nonfluorescein-labeled Ang II (Fig. 3B)
. These experiments show that monocytes have receptors for Ang II and that exogenous Ang II binds to receptors on monocyte cell surface.
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Figure 3. Demonstration of Ang II receptors on the cell surface of monocytes and binding of Ang II to monocytes. (A) Comparison of AT1 and AT2 on the membrane of monocytes incubated in the absence and presence of TNF- and GM-CSF at 0 and 24 h. (B) Binding of fluorescein-labeled Ang II to receptors on the cell surface of monocytes in the absence or presence of tenfold excess of nonfluorescein-labeled Ang II.
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- and GM-CSF-stimulated monocytes (Fig. 4A
). Moreover, MMP-1 levels were further enhanced when CGP-42112A was combined with [Sar1, Ala8]-Ang II. Further demonstration of receptor specificity was obtained through the use of the AT2 receptor antagonist PD123319 [24
], which completely blocked the TNF-- and GM-CSF-stimulated production of MMP-1 (Fig. 4B)
. The AT2 receptor antagonist also blocked the enhanced production of MMP-1 by 100 µM Ang I and Ang II (Fig. 4C)
. Furthermore, measurement of mRNA concentrations using RT-PCR 12 h after stimulation with TNF- and GM-CSF showed an increase in the transcript of MMP-1 with addition of Ang II and an inhibition with addition of PD123319 (Fig. 4D)
. These findings demonstrate that Ang II stimulates transcription and translation for MMP-1 through the AT2 receptor and that Ang II plays a central role in the regulation of MMP-1 production by monocytes stimulated with TNF- and GM-CSF.
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Figure 4. Ang II mediates its effects on MMP-1 production by cytokine-stimulated monocytes through the AT2 receptor. (A) Effect of Ang II AT2 receptor agonist CGP-42112A in the absence or presence of [Sar1, Ala8]-Ang II on MMP-1 production by monocytes stimulated with TNF- and GM-CSF. (B) Effect of the AT2 receptor antagonist PD123319 on MMP-1 production by TNF-- and GM-CSF-stimulated monocytes. (C) PD123319 inhibition of cytokine Ang I (100 µM) and Ang II (100 µM) stimulated MMP-1 production. (D, E) PD123319 (PD; 100 µM) decreases the ratio of MMP-1 to ß-actin transcription in monocytes stimulated with TNF- (T) and GM-CSF (G) plus Ang II (100 µM).
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- and GM-CSF-stimulated monocytes is regulated through a PGE2-cyclic adenosine monophosphate-dependent mechanism [15
]. To determine if Ang II mediated its effects through prostaglandins, the prostaglandin inhibitors indomethacin or aspirin were added to cultures treated with TNF- and GM-CSF and 100 µM Ang II (Fig. 5A
). Indomethacin or aspirin inhibited the Ang II-stimulated increase in monocyte MMP-1, indicating Ang II mediated its effect through prostaglandins. This conclusion was further supported by the ability of PGE2 to reverse the inhibition of MMP production by the AT2 receptor antagonist PD123319 (Fig. 5B)
. These findings agree with those shown previously in Figure 1B
, in which AGT-enhanced MMP production by stimulated monocytes was inhibited by indomethacin, and addition of PGE2 reversed the inhibition of MMP production.
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Figure 5. Ang II-mediated MMP-1 production occurs through a PGE2-dependent pathway. (A) Prostaglandin synthesis inhibitors indomethacin (10–6 M) or aspirin (10–6 M) were added to cytokine and Ang II-stimulated monocytes. (B) Reversal of PD123319 inhibition of MMP-1 production by PGE2 (10–7 M). (C) Indomethacin (Indo; 1 µM) or aspirin (Asp; 1 µM) decreases PGE2 production by monocytes stimulated with TNF- and GM-CSF (T&G) and Ang II (100 µM). (D) PD123319 (PD; 100 µM) suppresses PGE2 production, and the AT2 receptor agonist CGP-42112A (100 µM) enhances PGE2 production by monocytes stimulated with TNF- and GM-CSF or with Ang II (100 µM).
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- and GM-CSF-stimulated monocytes produced significantly more PGE2 when Ang II was added compared with cytokines alone, and addition of indomethacin or aspirin led to a significant decrease in Ang II-mediated PGE2 production (Fig. 5C)
. Moreover, significant increases in PGE2 were observed when CGP-42112A, an AT2 agonist, was added to monocytes stimulated with TNF- and GM-CSF. In contrast, addition of the AT2 antagonist PD123319 with TNF- and GM-CSF led to a marked decrease in PGE2 (Fig. 5D) . These findings demonstrate that Ang II signaling through the AT2 receptor leads to induction of MMP-1 through a PGE2-dependent pathway. |
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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produced by other monocytes [25
] and GM-CSF produced by endothelial cells [26
]. Subsequent production and exposure to Ang II lead to the stimulation of AT2 receptors and production of PGE2, resulting in the production of MMP-1. The MMP-1 produced in an in vivo setting may be involved in the degradation of the thin fibrous cap over the atheroma, resulting in the rupture of the plaque.
We have shown that when cytokine-activated monocytes are exposed to physiologic concentrations of AGT, there is a significant enhancement of MMP-1 production, and higher concentrations of Ang I and Ang II are required to produce a similar effect. AGT is a stable, inactive peptide, and Ang II is an active peptide that is quickly taken up by monocytes (Fig. 2A)
. Moreover, Ang II has its most potent effect on monocyte MMP-1 production several hours after stimulation with TNF- and GM-CSF. Thus, adding high concentrations of Ang II along with cytokines or adding physiologic concentrations of Ang II 6 h after stimulation or along with short-acting Ang receptor inhibitor resulted in enhancement of MMP-1 production.
The level of Ang II in the lesion is likely to be higher in patients with hypertension who have higher levels of circulating AGT. Thus, the higher levels of Ang II in patients with hypertension are more likely to induce monocytes that entered the atherosclerotic plaque to produce significantly more MMP-1. As MMP-1 has the ability to degrade the collagen in the fibrous cap of an atheroma, the increased level of monocyte MMP-1 production in response to cytokines and Ang II may lead to the rupture of the plaque and subsequent myocardial infarction or stroke. This mechanism may explain the reason for hypertension as a risk for acute coronary syndrome. Moreover, the beneficial effects of captopril in decreasing the incidence of myocardial infarction [2 , 27 ] may be a result of its effect on decreasing the amount of Ang II in the circulation by inhibiting the conversion of Ang I to Ang II and thus, preventing exposure of stimulated monocytes in the atherosclerotic lesion to high concentrations of Ang II.
Our findings demonstrate that Ang II mediates its effect on monocyte MMP-1 production through the AT2 receptor. Addition of AT2 receptor agonist along with TNF- and GM-CSF, cytokines found in atherosclerotic plaques, leads to a significant enhancement of MMP-1, and addition of an AT2 antagonist PD123319 blocks MMP-1. These observations suggest that MMP-1 production is dependent on AT2 receptor stimulation. Human AT2 receptors are found in brain, heart, vascular tissues, adrenal, kidney, and skin. They are found in human fetal tissues at high levels and subsequently decrease during development, except in the myometrium, where levels remain high until pregnancy [28
]. Moreover, the AT2 receptor is up-regulated in several pathologic conditions such as cardiac hypertrophy, myocardial infarction, cardiomyopathy, and congestive heart failure [29
]. All of the conditions, normal and pathologic, involve significant remodeling of the ECM. Although our studies demonstrate that the AT2 receptor is involved in the regulation of MMP-1 by monocytes, the AT1 receptor has been shown in be involved in MMP-9 production by monocytes as well as the message level of PGE2 synthase [30
]. This later study showed that Ang II directly stimulated MMP-9, whereas in our study, Ang II alone did not induce MMP-1 or PGE2 production unless the monocytes were activated by cytokines. Thus, AT2 receptor stimulation may lead to production of MMP-1 in these conditions and play an important role in remodeling.
This study adds to our understanding of MMP-1 production in human monocytes by showing that Ang II binding to the AT2 receptor causes an increase in PGE2 that leads to the production of MMP-1. Blocking PGE2 production by adding indomethacin or aspirin decreases the production of MMP-1 induced by TNF- and GM-CSF as well as the significant enhancement by Ang II. Moreover, there is a direct relation between the stimulation or inhibition of AT2 receptor signaling and PGE2 production. Aspirin has long been established to reduce mortality from cardiac disease [31
]. This study suggests an additional mechanism for the beneficial effect of aspirin in cardiac disease by inhibiting MMP-1 production by human monocytes in atherosclerotic plaques.
In conclusion, Ang II, through AT2 receptors and cyclooxygenases, plays a central role in production of MMP-1 by monocytes stimulated with TNF- and GM-CSF, which may lead to atherosclerotic plaque rupture. This pathway may be inhibited at several points, which include suppressing conversion of Ang I to Ang II with ACE inhibitors, blocking activation of AT2 receptors with an antagonist, and preventing production of PGE2 with cyclooxygenase inhibitors.
Received December 9, 2004; revised February 21, 2005; accepted March 15, 2005.
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, granulocyte-macrophage CSF, and IL-1 ß through prostaglandin-dependent and -independent mechanisms J. Immunol. 161,3071-3076 differentially regulates monocyte matrix metalloproteinase-1 and -9 through tumor necrosis factor- and caspase 8 J. Biol. Chem. 278,45406-45413This article has been cited by other articles:
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