Combined inhibition of CD14 and C3 in myocardial hypertrophy and heart failure induced by pressure overload
Heart failure (HF) involves activation of immune system and inflammatory signaling pathways. The complement system and Toll-like receptors (TLR) are two main upstream arms of the innate immune system. Interesting data obtained from our in vivo study (FOTS 7783) indicated that combined upstream inhibition of the TLR pathway (targeting CD14), and complement system(targeting C3), might be a suitable target in inflammatory disease. We want to investigate the effect C3KO, CD14KO and C3CD14KO mice in a model of myocardial hypertrophy and HF induced by aortic banding (AB).
Purpose: better understand the role of the complement system and CD14 in the inflammatory response after AB.
Expected adverse effects: surgical survival rate is 80-90%. Tightness of banding determines the degree of hypertrophy and the age of the mice affects the recovery rate. A few animals can experience weight loss; they will be monitored closely and regularly regarding pain/discomfort and development of severe HF necessitating administration of analgesia or euthanized, respectively.
Expected society/scientific benefits: HF is an important and increasing cause of cardiovascular morbidity and mortality. With a 5-year mortality of more than 50% it seems evident that important pathogenic mechanisms remain unchallenged. Inflammatory processes play an important role in the development and progression of chronic HF, contributing to the shift from adaptive to maladaptive remodeling.
The AB model will allow us to mimic human cardiovascular disease and elucidate fundamental signaling processes involved in the cardiac hypertrophic response and HF progression.
Number of mice: 288 male mice, C57Bl/6J background, 4 different genotypes, 3 time points.
Replacement:
No cellular models or other ex vivo models exist that can fully mimic complex multicellular and organ interacting changes occuring in the development of disease where inflammatory processes are involved. Pharmacological agents that blocks the complement system or/and toll-like receptors in mice are limited and, if available, not suitable for long term studies.
To study the interaction between these inflammatory pathways and the heart, and to follow disease progression, we are dependent on a mouse model.
Reduction:
We have experience with this model and the phenotype of the mice (FOTS number 5341, 7783, 8244). As a result, we can make a better prediction on the number of mice necessary for this experiment.
Furthermore, we have refined the methods for using heart tissue after sacrifice, and can use the same heart for histology, RNA and protein analysis.
Refinement:
The mice are handled by the same, trained researchers, assuming to reduce stress. We will follow well established methods regarding AB surgery, anaesthesia and analgesia. In addition, mice will be euthanized if body weight is reduced more than 15% of their original weight or they show signs of severe HF with inactivity and tachopnoea. Furthermore, we follow the guidelines for housing and environmental enrichment applicable to our department.
Purpose: better understand the role of the complement system and CD14 in the inflammatory response after AB.
Expected adverse effects: surgical survival rate is 80-90%. Tightness of banding determines the degree of hypertrophy and the age of the mice affects the recovery rate. A few animals can experience weight loss; they will be monitored closely and regularly regarding pain/discomfort and development of severe HF necessitating administration of analgesia or euthanized, respectively.
Expected society/scientific benefits: HF is an important and increasing cause of cardiovascular morbidity and mortality. With a 5-year mortality of more than 50% it seems evident that important pathogenic mechanisms remain unchallenged. Inflammatory processes play an important role in the development and progression of chronic HF, contributing to the shift from adaptive to maladaptive remodeling.
The AB model will allow us to mimic human cardiovascular disease and elucidate fundamental signaling processes involved in the cardiac hypertrophic response and HF progression.
Number of mice: 288 male mice, C57Bl/6J background, 4 different genotypes, 3 time points.
Replacement:
No cellular models or other ex vivo models exist that can fully mimic complex multicellular and organ interacting changes occuring in the development of disease where inflammatory processes are involved. Pharmacological agents that blocks the complement system or/and toll-like receptors in mice are limited and, if available, not suitable for long term studies.
To study the interaction between these inflammatory pathways and the heart, and to follow disease progression, we are dependent on a mouse model.
Reduction:
We have experience with this model and the phenotype of the mice (FOTS number 5341, 7783, 8244). As a result, we can make a better prediction on the number of mice necessary for this experiment.
Furthermore, we have refined the methods for using heart tissue after sacrifice, and can use the same heart for histology, RNA and protein analysis.
Refinement:
The mice are handled by the same, trained researchers, assuming to reduce stress. We will follow well established methods regarding AB surgery, anaesthesia and analgesia. In addition, mice will be euthanized if body weight is reduced more than 15% of their original weight or they show signs of severe HF with inactivity and tachopnoea. Furthermore, we follow the guidelines for housing and environmental enrichment applicable to our department.