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A Mouse Model of Vascularized Heterotopic Spleen Transplantation for Studying Spleen Cell Biology and Transplant Immunity
Published on: June 11, 2019
Splenic Ly6Chi monocytes contribute to adverse late post-ischemic left ventricular remodeling in heme oxygenase-1
Mateusz Tomczyk1, Izabela Kraszewska1, Krzysztof Szade1
1Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Krakow, Poland.
Insights
Heme oxygenase-1 (Hmox1) deficiency improves early survival after myocardial infarction by reducing cardiac rupture. However, it leads to worse heart function later due to prolonged inflammation, with the spleen playing a key role.
Area of Science:
- Cardiovascular Biology
- Immunology
- Cellular Stress Response
Background:
- Heme oxygenase-1 (Hmox1) is a key enzyme in heme catabolism, producing compounds with antioxidant and anti-inflammatory properties.
- While Hmox1 shows cardioprotective effects in myocardial infarction (MI) models, its role in resolving post-ischemic inflammation is not fully understood.
Purpose of the Study:
- To investigate the role of Hmox1 in monocyte/macrophage-mediated cardiac remodeling following MI.
- To elucidate the impact of Hmox1 deficiency on inflammatory responses and left ventricular (LV) function post-MI.
Main Methods:
- Utilized a permanent left anterior descending coronary artery ligation mouse model.
- Compared Hmox1 knockout (Hmox1-/-) mice with wild-type (WT, Hmox1+/+) controls.
- Assessed cardiac rupture, LV function, monocyte/macrophage infiltration, and inflammatory markers, including splenectomy effects.
Main Results:
- Hmox1-/- mice exhibited reduced early cardiac rupture and improved survival post-MI.
- Late-phase (7-21 days) post-MI showed worsened LV function in Hmox1-/- mice, associated with increased Ly6Chi monocytes and cardiac inflammation.
- Splenectomy in Hmox1-/- mice reduced inflammatory monocytes, cardiac macrophages, and improved LV function.
Conclusions:
- Hmox1 deficiency has dual effects on MI: it enhances early survival but promotes adverse late remodeling via prolonged inflammation.
- The spleen is identified as a significant contributor to these detrimental cardiovascular outcomes in Hmox1-deficient mice post-MI.
Abstract:
Heme oxygenase-1 (Hmox1) is a stress-inducible protein crucial in heme catabolism. The end products of its enzymatic activity possess anti-oxidative, anti-apoptotic and anti-inflammatory properties. Cardioprotective effects of Hmox1 were demonstrated in experimental models of myocardial infarction (MI). Nevertheless, its importance in timely resolution of post-ischemic inflammation remains incompletely understood. The aim of this study was to determine the role of Hmox1 in the monocyte/macrophage-mediated cardiac remodeling in a mouse model of MI. Hmox1 knockout (Hmox1-/-) and wild-type (WT, Hmox1+/+) mice were subjected to a permanent ligation of the left anterior descending coronary artery. Significantly lower incidence of left ventricle (LV) free wall rupture was noted between 3rd and 5th day after MI in Hmox1-/- mice resulting in their better overall survival. Then, starting from 7th until 21st day post-MI a more potent deterioration of LV function was observed in Hmox1-/- than in the surviving Hmox1+/+ mice. This was accompanied by higher numbers of Ly6Chi monocytes in peripheral blood, as well as higher expression of monocyte chemoattractant protein-1 and adhesion molecules in the hearts of MI-operated Hmox1-/- mice. Consequently, a greater post-MI monocyte-derived myocardial macrophage infiltration was noted in Hmox1-deficient individuals. Splenectomy decreased the numbers of circulating inflammatory Ly6Chi monocytes in blood, reduced the numbers of proinflammatory cardiac macrophages and significantly improved the post-MI LV function in Hmox1-/- mice. In conclusion, Hmox1 deficiency has divergent consequences in MI. On the one hand, it improves early post-MI survival by decreasing the occurrence of cardiac rupture. Afterwards, however, the hearts of Hmox1-deficient mice undergo adverse late LV remodeling due to overactive and prolonged post-ischemic inflammatory response. We identified spleen as an important source of these cardiovascular complications in Hmox1-/- mice.
