Cardiac resident macrophages are involved in hypoxia-induced postnatal cardiomyocyte proliferation

Abstract

Induction of cardiomyocyte proliferation, the most promising approach to reverse myocardial attrition, has been gaining importance as a therapy for cardiovascular disease. Hypoxia and macrophages were previously independently reported to promote cardiomyocyte proliferation in mice. However, whether hypoxia promotes cardiomyocyte proliferation in humans, and the association between hypoxia and macrophages in cardiomyocyte proliferation, have not to the best of our knowledge been previously investigated. The present study investigated the cardiomyocyte proliferation in 22 acyanotic and 29 cyanotic patients. Cardiomyocyte proliferation in a hypoxic mouse model (15% O2) was subsequently performed and the macrophage subsets were analyzed. A C-C chemokine receptor type 2 (CCR2) inhibitor was used to increase the number of resident macrophages in order to investigate the effect of macrophages on cardiomyocyte proliferation. The results demonstrated that cardiomyocyte proliferation in the cyanotic infant group was significantly increased compared with the acyanotic infant group and the hypoxia-treated C57BL/6J neonates confirmed the hypoxia-induced cardiomyocyte proliferation. However, hypoxia did not induce the proliferation of isolated cardiomyocytes. Notably, hypoxia treatment increased the number of cardiac resident macrophages in neonate hearts. Furthermore, increasing the number of resident macrophages significantly enhanced cardiomyocyte proliferation. In conclusion, postnatal hypoxia promoted cardiomyocyte proliferation in humans and animals, and cardiac resident macrophages may be involved in this process. Therefore, this novel mechanism may provide a promising strategy for cardiovascular disease treatment.

Sirt1 promotes autophagy and inhibits apoptosis to protect cardiomyocytes from hypoxic stress

“…The relatively normoxic ventricular tissues samples used as control were obtained from patients with ventricular septal defect combined with right ventricular outflow tract obstruction. The hypoxic ventricular tissue samples were obtained from patients with Tetralogy of Fallot (TOF) as previously described (22).…”

Cellular cross-talks in the diseased and aging heart

“…In contrast to the transient extracellular matrix that normally accompanies regeneration in salamander hearts, macrophage depletion resulted in a permanent, highly cross-linked extracellular matrix scar derived from alternative fibroblast activation and lysyl-oxidase enzymes [91]. Interestingly, cardiac resident macrophage-derived cytokines can promote CM proliferation in hypoxic neonates [92] suggesting an additional potential role of macrophages in CM replacement. However, in salamander hearts, macrophage depletion did not interfere with CM proliferation [91] indicating that CM replacement may be controlled by a macrophage-independent mechanism in this setting ( Fig.…”

Heterocellularity and Cellular Cross-Talk in the Cardiovascular System

“…Furthermore, photo-stimulation of channelrhodopsin-2-expressing macrophages was able to improve atrioventricular conduction ( 83 ). Liu et al ( 84 ) using a hypoxic mouse model and acyanotic vs. cyanotic patients, showed that postnatal hypoxia promoted cardiomyocyte proliferation and that cardiac resident macrophages may be involved in this process ( 35 ). Macrophages also communicate with other cell types in the myocardium, particularly with cardiac fibroblasts via the leucocyte surface antigen CD40 or the up-regulation of ICAM-1 and VCAM-1 ( 85 , 86 ).…”