scholarly journals Anti—Monocyte Chemoattractant Protein-1 Gene Therapy Protects against Focal Brain Ischemia in Hypertensive Rats

2004 ◽  
Vol 24 (12) ◽  
pp. 1359-1368 ◽  
Author(s):  
Yasuhiro Kumai ◽  
Hiroaki Ooboshi ◽  
Junichi Takada ◽  
Masahiro Kamouchi ◽  
Takanari Kitazono ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Gene Transfer ◽  
Brain Ischemia ◽  
Infarct Volume ◽  
Dominant Negative ◽  
Hypertensive Rats ◽  
Monocyte Chemoattractant Protein 1 ◽  
Monocyte Chemoattractant ◽  
Monocyte Chemoattractant Protein ◽  
Focal Brain Ischemia

Monocyte chemoattractant protein-1 (MCP-1) is expressed in the ischemic cortex after focal brain ischemia and appears to exacerbate ischemic damage. The authors examined the effect of gene transfer of dominant negative MCP-1, called 7ND, 90 minutes after induction of focal brain ischemia in hypertensive rats. Adenoviral vectors encoding mutant MCP-1 (Ad7ND; n = 11), or Escherichia coli β-galactosidase (AdlacZ; n = 17) as control were injected into the lateral ventricle of male spontaneously hypertensive rats. Both AdlacZ (n = 12) and Ad7ND (n = 6) administration provided transgene expression as early as 6 hours after injection and the expression further increased on day 1, followed by a sustained detection on day 5. Five days after ischemia, infarct volume (75 ± 13 mm3, n = 5, mean ± SD) significantly reduced to 72% of control (104 ± 22 mm3, n = 5, P < 0.05) by 7ND gene transfer. Numbers of leukocytes in the vessels (48.3 ± 32.9/cm2) and macrophage/monocyte infiltration (475.2 ± 125.5 /mm2) of the infarct area in the Ad7ND group were significantly less than those measured in the AdlacZ group (143.8 ± 72.1/cm2 and 671.8 ± 125.5/mm2, P < 0.05, respectively). In summary, the postischemic gene transfer of dominant negative MCP-1 attenuated the infarct volume and infiltration of inflammatory cells, suggesting potential usefulness of the anti–MCP-1 gene therapy.

Abstract 3964: Nanoparticle-Mediated Monocyte-Selective Transfection of Dominant-Negative Monocyte Chemoattractant Protein-1 (MCP-1) Gene Inhibits Plaque Rupture in ApoE-Deficient Mice

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Jun-ichiro Koga ◽  
Kensuke Egashira ◽  
Tetsuya Matoba ◽  
Kaori Hara ◽  
Hiroyuki Tsujimoto ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Plaque Rupture ◽  
Dominant Negative ◽  
Monocyte Chemoattractant Protein 1 ◽  
Monocyte Chemoattractant ◽  
Coronary Syndrome ◽  
Monocyte Chemoattractant Protein ◽  
Plaque Destabilization ◽  
Aortic Plaques ◽  
Deficient Mice

Preventing rupture of unstable plaque is the most effective strategy for acute coronary syndrome (ACS). Monocytes/macrophages play a key role in plaque destabilization and rupture. Monocyte chemoattractant protein-1 (MCP-1) and its receptor (CCR2) play an essential role in regulating monocyte recruitment and activation. Blockade of the MCP-1/CCR2 pathway by nanoparticle (NP)-mediated monocyte-selective transfection of dominant-negative MCP-1 (7ND) gene inhibits plaque rupture. We prepared bioabsorbable PLGA NP (mean diameter = 200 nm). Intravenous administration of NP incorporated with 7ND gene (5 mcg plasmid/1 mg PLGA) resulted in incorporation of NP via phagocytosis and gene transfer into CD11b + circulating monocytes, and suppressed monocyte function. We then examined the effect of 7ND-NP on plaque rupture of brachiocephalic arteries in apoE-deficient mice fed with high-fat diet and infused with angiotensin II (Figure A ). At 20 weeks, animals were divided into no treatment group and those treated weekly with intravenously 7ND-NP or FITC-NP (Figure B ). FITC-NP was detected in macrophages of destabilized brachiocephalic arterial plaques, but not in those of stable aortic plaques. 7ND-NP did not affect the size of atheroma, but did reduce the occurrence of plaque rupture (Figure C ), macrophage infiltration, and tissue factor expression. Blockade of MCP-1/CCR2 pathway by NP-mediated monocyte-targeting gene transfer stabilized atheroma and prevented plaque rupture. This nanotechnology platform may be a less invasive therapeutic strategy for stabilizing rupture-prone plaques and thus preventing ACS.

Monocyte Chemoattractant Protein-1 Expression in Aortic Tissues of Hypertensive Rats

Hypertension ◽  
1997 ◽  
Vol 30 (6) ◽  
pp. 1397-1402 ◽  
Author(s):  
Quinn Capers ◽  
R. Wayne Alexander ◽  
Pingping Lou ◽  
Hector De Leon ◽  
Josiah N. Wilcox ◽  
...  
Keyword(s):  
Hypertensive Rats ◽  
Monocyte Chemoattractant Protein 1 ◽  
Monocyte Chemoattractant ◽  
Monocyte Chemoattractant Protein

The MKK6/p38 Stress Kinase Cascade Is Critical for Tumor Necrosis Factor-–Induced Expression of Monocyte-Chemoattractant Protein-1 in Endothelial Cells

Blood ◽  
1999 ◽  
Vol 93 (3) ◽  
pp. 857-865 ◽  
Author(s):  
Matthias Goebeler ◽  
Karin Kilian ◽  
Reinhard Gillitzer ◽  
Manfred Kunz ◽  
Teizo Yoshimura ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Dominant Negative ◽  
Monocyte Chemoattractant Protein 1 ◽  
Monocyte Chemoattractant ◽  
Monocyte Chemoattractant Protein ◽  
Kinase Cascade ◽  
Stress Kinase ◽  
Necrosis Factor

Abstract Monocyte chemoattractant protein-1 (MCP-1), a member of the C-C subfamily of chemokines, is important for the local recruitment of leukocytes to sites of inflammatory challenge. Here, we investigated endothelial signaling pathways involving members of the mitogen-activated protein (MAP) kinase superfamily and studied their role for MCP-1 expression in endothelium. We show that tumor necrosis factor- (TNF-), a potent inflammatory activator of endothelium, leads to activation of MAP kinases ERK, p38, and JNK in human umbilical vein endothelial cells (HUVEC). Contribution of MAP kinase pathways to TNF-–induced synthesis of endothelial MCP-1 was then studied by pharmacologic inhibition and transient expression of dominant negative or constitutively active kinase mutants using flow cytometry, Northern blot, and luciferase reporter gene assays. Inhibition of Raf/MEK/ERK or SEK/JNK pathways had no significant effect on MCP-1 levels, whereas blocking the MKK6/p38 pathway by p38 inhibitors SB203580 or SB202190 or by a dominant negative mutant of MKK6, the upstream activator of p38, strongly inhibited TNF-–induced expression of MCP-1. Consistent with that finding, expression of wild-type or constitutively active MKK6 significantly enhanced the effect of limiting TNF- concentrations on MCP-1 synthesis. These data suggest a crucial role for the MKK6/p38 stress kinase cascade in TNF-–mediated endothelial MCP-1 expression.

The MKK6/p38 Stress Kinase Cascade Is Critical for Tumor Necrosis Factor-–Induced Expression of Monocyte-Chemoattractant Protein-1 in Endothelial Cells

Blood ◽  
1999 ◽  
Vol 93 (3) ◽  
pp. 857-865 ◽  
Author(s):  
Matthias Goebeler ◽  
Karin Kilian ◽  
Reinhard Gillitzer ◽  
Manfred Kunz ◽  
Teizo Yoshimura ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Dominant Negative ◽  
Monocyte Chemoattractant Protein 1 ◽  
Monocyte Chemoattractant ◽  
Monocyte Chemoattractant Protein ◽  
Kinase Cascade ◽  
Stress Kinase ◽  
Necrosis Factor

Monocyte chemoattractant protein-1 (MCP-1), a member of the C-C subfamily of chemokines, is important for the local recruitment of leukocytes to sites of inflammatory challenge. Here, we investigated endothelial signaling pathways involving members of the mitogen-activated protein (MAP) kinase superfamily and studied their role for MCP-1 expression in endothelium. We show that tumor necrosis factor- (TNF-), a potent inflammatory activator of endothelium, leads to activation of MAP kinases ERK, p38, and JNK in human umbilical vein endothelial cells (HUVEC). Contribution of MAP kinase pathways to TNF-–induced synthesis of endothelial MCP-1 was then studied by pharmacologic inhibition and transient expression of dominant negative or constitutively active kinase mutants using flow cytometry, Northern blot, and luciferase reporter gene assays. Inhibition of Raf/MEK/ERK or SEK/JNK pathways had no significant effect on MCP-1 levels, whereas blocking the MKK6/p38 pathway by p38 inhibitors SB203580 or SB202190 or by a dominant negative mutant of MKK6, the upstream activator of p38, strongly inhibited TNF-–induced expression of MCP-1. Consistent with that finding, expression of wild-type or constitutively active MKK6 significantly enhanced the effect of limiting TNF- concentrations on MCP-1 synthesis. These data suggest a crucial role for the MKK6/p38 stress kinase cascade in TNF-–mediated endothelial MCP-1 expression.

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