Toll‐interacting protein contributes to mortality following myocardial infarction through promoting inflammation and apoptosis

Background and Purpose Toll‐interacting protein ( T ollip) is an endogenous inhibitor of toll‐like receptors, a superfamily that plays a pivotal role in various pathological conditions, including myocardial infarction ( MI ). However, the exact role of T ollip in MI remains unknown. Experimental Approach MI models were established in T ollip knockout ( KO ) mice, mice with cardiac‐specific overexpression of human T ollip gene and in their T ollip +/+ and non‐transgenic controls respectively. The effects of T ollip on MI were evaluated by mortality, infarct size and cardiac function. Hypoxia‐induced cardiomyocyte damage was investigated in vitro to confirm the role of T ollip in heart damage. Key Results T ollip expression was dramatically up‐regulated in human ischaemic hearts and infarcted mice hearts. MI ‐induced mortality, infarct size and cardiac dysfunction were decreased in T ollip‐ KO mice compared with T ollip +/+ controls. Ischaemic hearts from T ollip‐ KO mice exhibited decreased inflammatory cell infiltration and reduced NF ‐κ B activation. T ollip depletion also alleviated myocardial apoptosis by down‐regulating pro‐apoptotic protein levels and up‐regulating anti‐apoptotic protein expressions in infarct border zone. Conversely, MI effects were exacerbated in mice with cardiac‐specific T ollip overexpression. This aggravated MI injury by T ollip in vivo was confirmed with in vitro assays. Inhibition of A kt signalling was associated with the detrimental effects of T ollip on MI injury; activation of A kt largely reversed the deleterious effects of T ollip on MI ‐induced cardiomyocyte death. Conclusions and Implications T ollip promotes inflammatory and apoptotic responses after MI , leading to increased mortality and aggravated cardiac dysfunction. These findings suggest that T ollip may serve as a novel therapeutic target for the treatment of MI .