Blockade of NKG2D / NKG2D ligands interaction as a novel therapeutic strategy against heart failure

[Speaker] Kotaro Matsumoto:1
[Co-author] Masanori Obana:1, Makiko Maeda:1, Hiroyuki Nakayama:1, Yasushi Fujio:1
1:Pharmaceutical Sciences, Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, Japan

It is widely accepted that cardiomyocyte death contributes to the onset and progression of heart failure, however, the mechanism remains to be fully elucidated. Accumulating evidence shows that immunoreactions are deeply involved in cardiovascular diseases. Here, we focused on immunosurveillance system, which eliminates damaged cells, such as infected or malignant cells. In this system, Natural Killer Group 2 member D (NKG2D), an activating receptor expressed on immune cells, including NK, NKT and γδT cells, causes apoptosis by recognizing NKG2D ligands (NKG2DLs) on the target cells. The aim of this study is to make clear the pathophysiological significance of NKG2D/NKG2DL-mediated cell death in post-infarction heart failure.

Methods and Results:
Myocardial infarction (MI) was generated by the occlusion of left anterior descending artery (LAD). The expression of NKG2D and NKG2DL, especially Rae-1ε, was concomitantly increased and reached the peak 3-7 days after MI. Consistently, the expression of perforin and granzyme B was also up-regulated after MI. Immunohistochemical staining showed that Rae-1 was expressed on the membranes of injured cardiomyocytes in the infarct and border area. In addition, Rae-1 was found to be induced by p53 because Rae-1 expression was suppressed in p53-/- mice. Flow cytometric analysis revealed that NKG2D-expressing immune cells which infiltrated into post-infarcted myocardium were mainly γδT cells. To clarify the pathophysiological role of NKG2D/NKG2DL interaction, post-MI mice were intraperitoneally injected with anti-Rae-1ε antibody. Anti-Rae-1ε antibody administration showed cardioprotective effects with reduced proportion of apoptotic cardiomyocytes, suppression of cardiac fibrosis, and attenuation of cardiac dysfunction. Finally, to exclude the possibility that anti-Rae-1ε antibody acted on organs other than the heart, we created tamoxifen-induced cardiac-specific Rae-1ε overexpressing mice and found that these mice demonstrated the susceptibility to post-infarct remodeling with the increase of cardiomyocyte apoptosis.

Immune cell-cardiomyocyte interaction via NKG2D/NKG2DL system induced cardiomyocyte death, leading to the progression of cardiac remodeling after MI. The blockade of NKG2D/NKG2DL signaling could be a promising therapeutic strategy against heart failure.

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