Abstract 8146: Gene Delivery of Suppressor of Cytokine Signaling 1 Decreases Myocardial Inflammation in Experimental Autoimmune Myocarditis
Introduction: Myocarditis and subsequent dilated cardiomyopathy are major cause of heart failure. Recent reports indicate that a subgroup of myocarditis patients may benefit from immune-targeted therapies. Suppressor of cytokine signaling 1 (SOCS1) plays a key role in the negative regulation of immune responses. We therefore hypothesized that overexpression of SOCS1 may have therapeutic effects in the treatment of myocarditis.
Methods and Results: Myocarditis was induced by subcutaneous immunization with cardiac specific peptides derived from α myosin heavy chain (MyHC-α) in BALB/c mice. Plasmid DNA encoding SOCS1 (pSOCS1) or empty plasmid was injected intraperitoneally into mice on days 0, 5 and 10 after induction of myocarditis. The heart-to-body weight ratios in pSOCS1-treated mice were significantly decreased compared with control plasmid-received mice (4.8±0.2 mg/g vs 6.2±0.5 mg/g; n=5, P<0.05). pSOCS1-treated mice had fewer infiltrating CD45+ cells in the heart than control plasmid-injected mice analyzed by flow cytometry (4.0±0.6 % of total cells vs 36.4±10.6 % of total cells; n=5, p<0.05). Echocardiography showed preserved contractile function in pSOCS1-treated mice compared with control plasmid-treated mice (fractional shortening: 36±3 % vs 22±1 %; n=9, p<0.01). Western blot analysis of DCs from pSOCS1-treated mice revealed decreased phosphorylation of STAT1. In the culture supernatant of DCs from pSOCS1-treated mice, the amount of proinflammatory cytokines was decreased (IL-6: 472±11 pg/ml vs 762±20 pg/ml, p<0.01; TNF-α: 1.9±0.0 ng/ml vs 3.9±0.1 ng/ml, p<0.01). MyHC-α-specific CD4+ T cells were isolated from myocarditis mice and co-cultured with MyHC-α-pulsed DCs from pSOCS1- or control plasmid-treated mice. The proliferative responses of CD4+ T cells co-cultured with DCs from pSOCS1-treated mice were much lower than with DCs from control plasmid-received mice assessed by measuring [3H]-thymidine uptake (1,401±393 cpm vs 2,584±213 cpm, p<0.05).
Conclusion: SOCS1 gene therapy reduced cardiac inflammation and improved cardiac performance in experimental autoimmune myocarditis. Our data suggested that in vivo gene delivery of SOCS1 suppresses the functional capacity of DCs to prime and expand autoreactive CD4+ T cells.
- © 2011 by American Heart Association, Inc.