Key result
Stabilin-1 knockout increases cardiac mortality and necrosis in mice following CVB3 viral challenge.
Why the study?
Viral myocarditis lacks therapies, and understanding the cellular and molecular steps of cardiac inflammation is essential to develop new treatments.
Stabilin-1 is essential for monocyte recruitment and adhesion via fibronectin, protecting against exaggerated inflammation and mortality in viral myocarditis.
Answers are grounded in this paper and cite their sources.
May guide targeted anti-inflammatory therapies in viral myocarditis; leaves open clinical translation.
Purpose: Viral myocarditis is a life-threatening disease characterized by severe cardiac inflammation that can result in sudden death or congestive heart failure in previously healthy adults, and there are no current therapies. Inflammatory cell recruitment is necessary to eliminate the virus but also plays a large role in the pathophysiology therefore understanding the cellular and molecular steps of cardiac inflammation is essential in order to develop new therapies. Methods: In the coxsackie B3 (CVB3) murine model of viral myocarditis, transcript levels of stabilin-1, a transmembranal glycoprotein, increased 3-fold in heart tissue at 9 days post infection. Immunohistochemical detection of stabilin-1 showed an increase of stabilin-1 expression in mouse heart tissue after CVB3 infection and in endomyocardial biopsies from patients with viral myocarditis. Furthermore, stabilin-1 was expressed on mac-3 positive cells in the mouse model and CD68-positve cells in the human biopsies. Stabilin-1 null (KO) mice showed increased cardiac related mortality when challenged with the CVB3 virus in comparison to wild type (WT) mice. Histological analysis of the heart showed that the stabilin-1 KO mice had increased cardiomyocyte necrosis and CD3+ lymphocyte infiltration but lower levels of macrophages cells, in comparison to WT animals. In vitro, Stabilin-1 KO monocytes (cd11b+ cells) had a significant decreased adherence to endothelial cells as compared to WT cells. Fibronectin was identified as the binding partner of stabilin-1, through a 2-yeast hybrid screen and GST-pulldown. Furthermore, Stabilin-1 KO monocytes (cd11b+ cells) had a significant decreased adherence to fibronectin -coated plastic as compared to WT cells. Conclusions: This study shows that the transmembranal glycoprotein Stabilin-1 is up regulated during myocarditis, both in the animal model and in patients with acute fulminant myocarditis. Stabilin-1 is needed for the recruitment of monocytes to the site of infection and interacts with fibronectin in order for monocytes to adhere. These data demonstrate that Stabilin-1 and monocyte recruitment are necessary in order to eliminate the virus and prevent exaggerated inflammation during viral myocarditis.
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Papageorgiou et al. (2013) studied Viral myocarditis. Stabilin-1 deficiency (Stabilin-1 KO) vs. Wild type (WT) was evaluated on Cardiac related mortality. Stabilin-1 null mice showed increased cardiac-related mortality, cardiomyocyte necrosis, and CD3+ lymphocyte infiltration compared to wild-type mice when challenged with CVB3 virus.
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