Abstract
Inflammation resulting from virus infection is the cause of myocarditis; however, the precise mechanism by which inflammation induces cardiac dysfunction is still unclear. In this study, we investigated the contribution of insulin signalling to inflammatory cardiac dysfunction induced by the activation of signalling by NF-κB, a major transcriptional factor regulating inflammation. We generated mice constitutively overexpressing kinase-active IKK-β, an essential kinase for NF-κB activation, in cardiomyocytes (KA mice). KA mice demonstrated poor survival and significant cardiac dysfunction with remarkable dilation. Histologically, KA hearts revealed increased cardiac apoptosis and fibrosis and the enhanced recruitment of immune cells. By molecular analysis, we observed the increased phosphorylation of IRS-1, indicating the suppression of insulin signalling in KA hearts. To evaluate the contribution of insulin signalling to cardiac dysfunction in KA hearts, we generated mice with cardiac-specific suppression of phosphatase and tensin homologue 10 (PTEN), a negative regulator of insulin signalling, in the KA mouse background (KA-PTEN). The suppression of PTEN successfully improved insulin signalling in KA-PTEN hearts, and interestingly, KA-PTEN mice showed significantly improved cardiac function and survival. These results indicated that impaired insulin signalling underlies the mechanism involved in inflammation-induced cardiac dysfunction, which suggests that it may be a target for the treatment of myocarditis.
Highlights
Myocarditis is a critical disease characterized by significant cardiac dysfunction and can eventually lead to inflammatory dilated cardiomyopathy (DCMi)[1,2,3]
These results indicate that IKKβ-nuclear factor-κB (NF-κB) signalling was successfully activated in kinase specific to cardiomyocytes (KA) hearts
We have shown that cardiomyocyte-specific IKKβ activation induced insulin resistance as well as severe cardiac dysfunction, and the reduction of insulin resistance by the suppression of phosphatase and tensin homologue 10 (PTEN) alleviated cardiac dysfunction and enhanced survival
Summary
Myocarditis is a critical disease characterized by significant cardiac dysfunction and can eventually lead to inflammatory dilated cardiomyopathy (DCMi)[1,2,3]. Maier et al reported that activation of IKKβ/ NF-κB in the cardiomyocytes induced the phenotype of DCMi in mice[6,11] As indicated in those reports, there is consensus on the involvement of the inflammation in the progression of DCMi; targeting NF-κB signalling with immune suppressive drugs is not always effective for treatment of DCMi12,13. It has been reported that metformin, a widely-used anti-diabetic drug, attenuated myocarditis induced by endotoxin in mice[20] and associated with lower mortality in ambulatory patients with diabetes and heart failure[21]
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