Cardiac Overexpression of CXCL10 Causes Spontaneous Leukocyte Infiltration but Not Cardiac Dysfunction
J Yuan, T Lim, JQ He, YJ Wang, HF Zhang, A Sall, Z Liu, B McManus, DC Yang. Medical College of Georgia, Augusta, GA; The James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, Vancouver, BC, Canada
Background: The essential role of chemokines in dilated cardiomyopathy (DCM) has been demonstrated by recent studies. We previously showed the upregulation of cystein-x-cystein (CXC) chemokine ligand 10 (CXCL10) in Coxsackievirus B3 (CVB3)-induced myocarditis, a major cause of DCM.
Design: To explore the contribution of CXCL10 to CVB3-induced myocarditis and associated DCM, we performed functional analyses using newly generated transgenic mice (Tg) that cardiac-specifically overexpress CXCL10.
Results: A transgenic mouse model with cardiac-specific overexpression of CXCL10 was generated. The cardiac specific upregulation of CXCL10 was confirmed by PCR, RT-PCR, in situ hybridization, and Western blot analyses. Cardiac-specific expression of CXCL10 resulted in spontaneous infiltration of CD4+ T cell, CD8+ T cell, and NK cell in perivascular and interstitial regions of the myocardium as compared to control wild type littermates by both real time qRT-PCR and immunohistochemical staining. The number of infiltrations was age-dependent, with the greatest number in older Tg mice, but barely any in four-week-old mice. Further, the expression levels of IFN-, and counterinflammatory IL-10 cytokine in Tg hearts were significantly elevated as compared to that in wild type mouse hearts, but the expression levels of the pro-inflammatory cytokines (TNF-, IL-4, IL-5, IL-6, IL-12) were unchanged. Despite the presence of mononuclear cell infiltrations and limited mRNA upregulation of IFN- and IL-10 in the myocardium, there were no discernible pathological alterations in the hearts of Tg mice, as revealed by (i) cardiac troponin I levels, a serum marker of myocyte injury; (ii) echocardiography, a measure of heart ejection fraction; and (iii) heart mass/body weight.
Conclusions: These findings indicate that CXCL10 primarily directs T cells and NK cells to the myocardium, and is associated with minor defense immunity but is insufficient to cause cardiac dysfunction.
Tuesday, March 10, 2009 1:00 PM
Poster Session IV # 55, Tuesday Afternoon