Neutralizing granzyme b for providing cardiac protection to subjects undergoing myocardial infarction

Abstract

The present invention relates to a method of providing cardiac protection to a subject having undergone myocardial infarction, the method comprising administering to the subject a therapeutically effective amount of a granzyme B inhibitor. The inventor proves that after acute MI occurs in a mouse, CD8 + T lymphocytes are rapidly collected and activated in ischemic heart tissue, granzyme B is released, and myocardial cell apoptosis and myocardial function deterioration are caused. The depletion of antibody-mediated (CD8 + T lymphocytes) CD8 + T lymphocytes reduces the content of granzyme B in cardiac muscle and apoptosis and inflammatory responses. The mAb-mediated CD8 depletion will limit myocardial damage and improve cardiac function. These effects are reproduced in mice that are deficient in CD8 + T cell selective granzyme B. Granzyme B is also produced by other cell types, such as NK cells. Overall granzyme B deletion (GzmB-/-mouse) can reduce apoptosis in cardiac muscle, reduce local pro-inflammatory markers and ultimately limit infarction area after MI. The inventor also proves that the increase of the circulation level of granzyme B in an acute MI patient indicates that the mortality risk is increased during one-year follow-up visit. This work reveals the previously unexpected pathogenic effect of granzyme B following acute ischemia and identifies a new therapeutic target for this destructive condition.

Description

technical field [0001] The present invention belongs to the field of medicine, especially cardiology. Background technique [0002] Acute myocardial ischemia and reperfusion following primary PCI is responsible for cardiac tissue damage leading to deleterious myocardial remodeling and heart failure. Many advances have been made in the early management of acute coronary thrombotic occlusion, including rapid mechanical restoration of coronary blood flow and antiplatelet therapy [1]. For myocardial infarction (MI), a gradual decrease in early mortality over time has been observed in the United States [2] and Europe [3]. However, the long-term effects of ischemia-related cardiac injury remain a clinical and societal concern, including an increased risk of arrhythmia, heart failure, and recurrent hospitalization [4]. Therefore, current efforts are directed at targeting the pathophysiological pathways involved in post-ischemic cardiac remodeling [5,6]. [0003] A large body of ...

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However, the mechanism of CD8-medi...

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