Rationale: Post ischemic heart failure is the consequence of pathological remodeling after myocardial ischemic damage. T lymphocyte mediated immune response is known to play an important role in post-ischemic cardiac remodeling. T regulatory lymphocytes (Treg) are a subpopulation of T helper lymphocytes with a regulatory and immunosuppressive role. Heme oxygenase (HO)-1 induction improves heart function after ischemic damage by its anti-inflammatory, anti-oxidative and anti-apoptotic effect. Aim: Aim of this study was to assess the role of HO-1 mediated increased levels of T-reg lymphocytes in post-ischemic cardiac remodeling. Methods: We compared the effect of HO-1 induction on post-ischemic heart failure induced by left anterior coronary artery ligation in T-lymphocytes immunodeficient mice (SCID) and in immunocompetent mice (C57). Mice were divided into 4 groups: sham, myocardial infarction (MI), MI treated with the HO-1 inducer cobalt protoporphyrin (CoPP) with and without the HO activity inhibitor stannous mesoporphyrin (SnMP). 30 days after surgery all mice underwent echocardiography and an assessment of T-lymphocyte subpopulations via fluorescence activated cell sorting (FACS). Results: Mice with MI had increased levels of inflammatory cytokines (p<0.05), significant myocardial fibrosis (SCID: 3.9±0.9% vs 0.7±0.1%; p<0.02) and lower capillary density (SCID: 1.2±0.7% vs 4.3±0.9%; p<0.01) compared to controls. Echocardiography showed that the left ventricle end diastolic area (EDA) was significantly reduced in CoPP treated compared to MI groups (EDA: MI: 0.22±0.02 cm; MI+CoPP: 0.17±0.03 cm; -13%, p<0.01) and the beneficial effect of HO-1 induction was more evident in SCID mice (EDA: MI: 0.19±0.02 cm; MI+CoPP: 0.10±0.01 cm, -25%, p<0.01). In CoPP treated C57 mice the T-reg subpopulation was significantly increased (20±3% vs 5±3%; p<0.01). All these beneficial effects were reversed by SnMP. Conclusion: HO-1, via its effect on T-cell mediated immunity, reverses dysfunctional remodeling and enhances peri-infarct survival in the post-ischemic myocardium. Targeted enhancement of T-reg cells via HO- induction could thus provide adjuvant avenues for reducing morbidity and mortality in patients with post-MI heart failure. Author Disclosures: P. Pesce: None. S.J. Peterson: None. R. Rezzani: None. M. Boldrin: None. D. Sacerdoti: None. N.G. Abraham: None. Key Words: Heart failure • Remodeling • Oxidative stress • Immunologic factors
Essential Role of Immunosuppressive T-Regulatory Cells in Improving Heart Function in Post-Ischemic Myocardium via Up-Regulation of Heme-Oxygenase 1
David Sacerdoti;
2012-01-01
Abstract
Rationale: Post ischemic heart failure is the consequence of pathological remodeling after myocardial ischemic damage. T lymphocyte mediated immune response is known to play an important role in post-ischemic cardiac remodeling. T regulatory lymphocytes (Treg) are a subpopulation of T helper lymphocytes with a regulatory and immunosuppressive role. Heme oxygenase (HO)-1 induction improves heart function after ischemic damage by its anti-inflammatory, anti-oxidative and anti-apoptotic effect. Aim: Aim of this study was to assess the role of HO-1 mediated increased levels of T-reg lymphocytes in post-ischemic cardiac remodeling. Methods: We compared the effect of HO-1 induction on post-ischemic heart failure induced by left anterior coronary artery ligation in T-lymphocytes immunodeficient mice (SCID) and in immunocompetent mice (C57). Mice were divided into 4 groups: sham, myocardial infarction (MI), MI treated with the HO-1 inducer cobalt protoporphyrin (CoPP) with and without the HO activity inhibitor stannous mesoporphyrin (SnMP). 30 days after surgery all mice underwent echocardiography and an assessment of T-lymphocyte subpopulations via fluorescence activated cell sorting (FACS). Results: Mice with MI had increased levels of inflammatory cytokines (p<0.05), significant myocardial fibrosis (SCID: 3.9±0.9% vs 0.7±0.1%; p<0.02) and lower capillary density (SCID: 1.2±0.7% vs 4.3±0.9%; p<0.01) compared to controls. Echocardiography showed that the left ventricle end diastolic area (EDA) was significantly reduced in CoPP treated compared to MI groups (EDA: MI: 0.22±0.02 cm; MI+CoPP: 0.17±0.03 cm; -13%, p<0.01) and the beneficial effect of HO-1 induction was more evident in SCID mice (EDA: MI: 0.19±0.02 cm; MI+CoPP: 0.10±0.01 cm, -25%, p<0.01). In CoPP treated C57 mice the T-reg subpopulation was significantly increased (20±3% vs 5±3%; p<0.01). All these beneficial effects were reversed by SnMP. Conclusion: HO-1, via its effect on T-cell mediated immunity, reverses dysfunctional remodeling and enhances peri-infarct survival in the post-ischemic myocardium. Targeted enhancement of T-reg cells via HO- induction could thus provide adjuvant avenues for reducing morbidity and mortality in patients with post-MI heart failure. Author Disclosures: P. Pesce: None. S.J. Peterson: None. R. Rezzani: None. M. Boldrin: None. D. Sacerdoti: None. N.G. Abraham: None. Key Words: Heart failure • Remodeling • Oxidative stress • Immunologic factors
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