Introduction: Post-infarction cardiomyopathy has been ascribed to chronic inflammation, increased oxidative stress and insufficient angiogenesis. T lymphocyte mediated immune response plays an important role in post-infarct 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-oxidative effect. To assess the role of the HO-1 mediated increased levels of T-reg lymphocytes in immunosuppressed mice in a model of post-infarcted heart failure.
Methods: We compared the effect of HO-1 induction on post-infarction myocardium induced by left anterior coronary artery ligation in T-lymphocyte immunosuppressed mice (BALB SCID). 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). Thirty days after surgery all mice underwent echocardiography, immunohistochemistry and an assessment of T-lymphocyte subpopulations (Treg cells) via fluorescence activated cell sorting (FACS).
Results: Mice with MI had increased levels of inflammatory cytokines (p<0.05) and lower capillary density (SCID: 1.2±0.7% vs control: 4.3±0.9%; p<0.01). Left ventricle end diastolic area (EDA) was reduced in CoPP treated compared to the MI group (EDA: MI: 0.22 ±0.02 cm; MI+CoPP: 0.17±0.03 cm; p<0.01). In CoPP treated SCID mice the T-reg subpopulation measured by FACS analysis (20±3% vs 5±3%; p<0.01) and immunohistochemistry (p<0.02) was significantly increased as compared to the MI group. Increased expression of the angiogenic markers VEGF, FGF and ETS-1 (p<0.02) was found in CoPP treated animals as compared to MI animals. These beneficial effects were reversed by SnMP.
Conclusion: Upregulation of HO-1 increases T regulatory cells, reverses dysfunctional remodeling and enhances angiogenesis and peri-infarct survival in the post-infarction myocardium in immunosuppressed mice. Targeted enhancement of T-reg cells via HO-1 induction suggests adjuvant avenues for reducing morbidity and mortality in patients with post-MI heart failure.