Abstract
The transcription factor signal transducer and activator of transcription 3 (STAT3) is an important mediator of the inflammatory process. We investigated the role of STAT3 in viral myocarditis and its possible role in the development to dilated cardiomyopathy. We used STAT3-deficent mice with a cardiomyocyte-restricted knockout and induced a viral myocarditis using Coxsackievirus B3 (CVB3) which induced a severe inflammation during the acute phase of the viral myocarditis. A complete virus clearance and an attenuated inflammation were examined in both groups WT and STAT3 KO mice 4 weeks after infection, but the cardiac function in STAT3 KO mice was significantly decreased in contrast to the infected WT mice. Interestingly, an increased expression of collagen I was detected in STAT3 KO mice compared to WT mice 4 weeks after CVB3 infection. Furthermore, the matrix degradation was reduced in STAT3 KO mice which might be an explanation for the observed matrix deposition. Consequently, we here demonstrate the protective function of STAT3 in CVB3-induced myocarditis. Since the cardiomyocyte-restricted knockout leads to an increased fibrosis, it can be assumed that STAT3 signalling in cardiomyocytes protects the heart against increased fibrosis through paracrine effects.
Highlights
Acute viral myocarditis is a frequent cause of sudden cardiac death and can later progress to dilated cardiomyopathy (DCM) due to the chronic inflammatory process
To study the cytokine response induced by intraperitoneal Coxsackievirus B3 (CVB3) infection, the mRNA expression levels in cardiac tissue of infected and non infected was significantly increased (WT) and signal transducer and activator of transcription 3 (STAT3) KO mice were analysed
To study the relevance of the signal transducer and activator of transcription molecule 3 (STAT3) in CVB3-induced myocarditis, we examined mice with a cardiomyocyterestricted STAT3 deletion
Summary
Acute viral myocarditis is a frequent cause of sudden cardiac death and can later progress to dilated cardiomyopathy (DCM) due to the chronic inflammatory process. The inflammatory process is needed to control the acute viral infection, but, on the other hand, prolonged inflammation in the subacute phase of the disease will lead to adverse cardiac remodelling. The members of the IL-6-type cytokine family bind to plasma membrane receptor complexes containing the signal transducing 130 kDa glycoprotein (gp130) that are ubiquitously expressed in most tissues including the heart. Ligand binding to this receptor subsequently leads to the phosphorylation of STAT3 which is translocated into the nucleus [5]. Beyond 9 months, the STAT3 KO mice show increased interstitial fibrosis, and, at 12 months, the hearts were dilated [14, 15], suggesting a role for STAT3 in cardiac remodelling and the progression to DCM
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