JOURNAL ARTICLE

Critical role for monocyte chemoattractant protein-1 and macrophage inflammatory protein-1alpha in induction of experimental autoimmune myocarditis and effective anti-monocyte chemoattractant protein-1 gene therapy

Stefan Göser, Renate Ottl, Alexander Brodner, Thomas J Dengler, Jan Torzewski, Kensuke Egashira, Noel R Rose, Hugo A Katus, Ziya Kaya
Circulation 2005 November 29, 112 (22): 3400-7
16316965

BACKGROUND: Autoimmune myocarditis is a principal cause of heart failure among young adults and is often a precursor of dilated cardiomyopathy. Monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1alpha (MIP-1alpha) are potent chemotactic factors for mononuclear cells. The inflammatory infiltrate observed in myocardial lesions of myocarditis consists of >70% mononuclear cells. To determine their critical role in the pathogenesis of myocarditis, we inhibited mononuclear cell activation and migration to see if it would affect disease severity and disease prevalence in experimental autoimmune myocarditis (EAM).

METHODS AND RESULTS: In this report, we demonstrated that blockade of MCP-1 or MIP-1alpha with monoclonal antibodies significantly reduced severity of myocarditis in BALB/c mice immunized with cardiac myosin. Similar results were obtained when CCR2-/- and CCR5-/- mice were used. In CCR2-/- mice, not only disease severity but also disease prevalence was reduced. To further inhibit mononuclear cell activation and migration, we transfected the mice before inducing EAM with a dominant-negative inhibitor of MCP-1 gene (7ND). This transfection significantly reduced the disease severity, decreased mRNA expression levels, especially of the chemokines RANTES, MIP-2, IP-10, MCP-1, T-cell activation gene 3, and eotaxin in the myocardium, and resulted in a reduction in cardiac myosin-induced interleukin-1 and interleukin-4 and in an increase in interferon-gamma and interleukin-10 cytokine production by splenocytes.

CONCLUSIONS: Overall, these findings suggest that the chemokines MCP-1 and MIP-1alpha, acting through their receptors CCR2 and CCR5, are important in the induction of EAM and that inhibition of MCP-1 with 7ND gene transfection significantly reduced disease severity. This strategy may be a new feasible form of gene therapy against autoimmune myocarditis.

Full Text Links

Find Full Text Links for this Article

Discussion

You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Remove bar
Read by QxMD icon Read
16316965
×

Save your favorite articles in one place with a free QxMD account.

×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"