Abstract
Cardiac tissue remodeling in the course of chronic left ventricular hypertrophy requires phagocytes which degrade cellular debris, initiate and maintain tissue inflammation and reorganization. The dynamics of phagocytes in left ventricular hypertrophy have not been systematically studied. Here, we characterized the temporal accumulation of leukocytes in the cardiac immune response by flow cytometry and fluorescence microscopy at day 3, 6 and 21 following transverse aortic constriction (TAC). Cardiac hypertrophy due to chronic pressure overload causes cardiac immune response and inflammation represented by an increase of immune cells at all three time points among which neutrophils reached their maximum at day 3 and macrophages at day 6. The cardiac macrophage population consisted of both Ly6Clow and Ly6Chigh macrophages. Ly6Clow macrophages were more abundant peaking at day 6 in response to pressure overload. During the development of cardiac hypertrophy the expression pattern of adhesion molecules was investigated by qRT-PCR and flow cytometry. CD11b, CX3CR1 and ICAM-1 determined by qRT-PCR in whole cardiac tissue were up-regulated in response to pressure overload at day 3 and 6. CD11b and CX3CR1 were significantly increased by TAC on the surface of Ly6Clow but not on Ly6Chigh macrophages. Furthermore, ICAM-1 was up-regulated on cardiac endothelial cells. In fluorescence microscopy Ly6Clow macrophages could be observed attached to the intra- and extra-vascular vessel-wall. Taken together, TAC induced the expression of adhesion molecules, which may explain the accumulation of Ly6Clow macrophages in the cardiac tissue, where these cells might contribute to cardiac inflammation and remodeling in response to pressure overload.
Highlights
Cardiovascular diseases are among the leading causes of death worldwide
We studied the dynamics of phagocyte accumulation following cardiac hypertrophy using a murine model of transverse aortic constriction (TAC)
Our findings highlight the dynamic changes of the cardiac immune response during the development of Left ventricular (LV) hypertrophy, which were characterized by significantly increased immune cell numbers within the first 21 days after TAC
Summary
Cardiovascular diseases are among the leading causes of death worldwide. Left ventricular (LV) hypertrophy is a main determinant of morbidity and mortality as it occurs in response to various stimuli, including systemic arterial hypertension, aortic stenosis, or remodeling of the myocardium after myocardial infarction (MI) [1]. The sensing of a Toll-like-receptor 7 dependent danger signals triggered the intravascular retention of Ly6Clow monocytes by the endothelium, requiring CX3CR1 expression by Ly6Clow monocytes and CD11b [27] These results suggest that Ly6Clow monocytes behave as sentinels in the vessels, rarely extravasating in comparison to Ly6Chigh monocytes following Listeria infections [26], surveying the integrity of the endothelium. Their impact in orchestrating immune responses under sterile conditions remained undescribed, yet [27]. Referring to the findings observed in response to MI we proposed temporally coordinated invasion of different types of monocytes This may be explained by a dynamic expression of adhesion molecules on both partner endothelial cells as well as leukocytes
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