Molecular mechanisms mediating inflammation in vascular disease: Special reference to monocyte chemoattractant protein-1

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Abstract

There are several clinical challenges for the treatment of intractable cardiovascular diseases, including restenosis, atherosclerotic complications resulting from plaque rupture, severe tissue ischemia, and heart failure. Emerging evidence suggests that an inflammatory process is involved in the pathogenesis of such intractable diseases. In particular, inflammatory responses to arterial injury, which cause continuous recruitment and activation of monocytes mainly through activation of the monocyte chemoattractant protein-1 (MCP-1) pathway, have a central role in restenosis and atherogenesis. We recently devised a new strategy for anti-MCP-1 therapy by transfecting an N-terminal deletion mutant of the MCP-1 gene into skeletal muscles. This mutant MCP-1 lacks the N-terminal amino acids 2 to 8, called 7ND, and works as a dominant-negative inhibitor of MCP-1. We demonstrated that 7ND gene transfer suppresses monocyte infiltration/activation after arterial injury and markedly inhibits experimental restenosis in animals after balloon injury or stent placement. Furthermore, 7ND gene transfer not only attenuated the development of early atherosclerotic lesions but also limited progression of preexisting atherosclerotic lesions and changed the lesion composition into a more stable phenotype in hypercholesterolemic mice. Vascular inflammation mediated by MCP-1 might create a positive feedback loop to enhance restenotic and atherosclerotic changes through activating lesional monocytes. Therefore, vascular inflammation mediated by MCP-1 has a central role in the development of experimental restenosis, atherosclerosis, and plaque destabilization, leading to acute coronary syndrome. This strategy for gene therapy might be useful against human restenosis, thereby opening a new therapeutic window for antirestenosis and antiatherosclerosis paradigms.

Original languageEnglish
Pages (from-to)834-841
Number of pages8
JournalHypertension
Volume41
Issue number3 II
DOIs
Publication statusPublished - Mar 1 2003

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Chemokine CCL2
Vascular Diseases
Inflammation
Monocytes
Blood Vessels
Atherosclerosis
Wounds and Injuries
Genes
Mutant Proteins
Acute Coronary Syndrome
Genetic Therapy
Stents
Rupture
Skeletal Muscle
Cardiovascular Diseases
Therapeutics
Ischemia
Heart Failure
Phenotype
Amino Acids

All Science Journal Classification (ASJC) codes

  • Internal Medicine

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Molecular mechanisms mediating inflammation in vascular disease : Special reference to monocyte chemoattractant protein-1. / Egashira, Kensuke.

In: Hypertension, Vol. 41, No. 3 II, 01.03.2003, p. 834-841.

Research output: Contribution to journalArticle

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