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Cardiac resident macrophages are involved in hypoxia‑induced postnatal cardiomyocyte proliferation
Bo Liu1, Hua-Gang Zhang1, Yun Zhu1
1Institute of Cardiovascular Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China.
Insights
Postnatal hypoxia promotes heart cell regeneration in infants and mice. Cardiac resident macrophages are key, suggesting a new therapy for cardiovascular disease.
Area of Science:
- Cardiovascular Research
- Regenerative Medicine
- Immunology
Background:
- Cardiomyocyte proliferation is crucial for treating cardiovascular disease.
- Hypoxia and macrophages independently promote cardiomyocyte proliferation in mice.
- The role of hypoxia and macrophages in human cardiomyocyte proliferation is unknown.
Purpose of the Study:
- Investigate hypoxia's effect on human cardiomyocyte proliferation.
- Examine the association between hypoxia and macrophages in this process.
- Explore therapeutic potential for cardiovascular disease.
Main Methods:
- Analyzed cardiomyocyte proliferation in cyanotic and acyanotic infants.
- Utilized a hypoxic mouse model (15% O2) and analyzed macrophage subsets.
- Administered a CCR2 inhibitor to modulate resident macrophage populations.
Main Results:
- Significantly increased cardiomyocyte proliferation in cyanotic infants versus acyanotic.
- Confirmed hypoxia-induced cardiomyocyte proliferation in mouse neonates.
- Hypoxia increased cardiac resident macrophages, enhancing proliferation.
Conclusions:
- Postnatal hypoxia promotes cardiomyocyte proliferation in humans and animals.
- Cardiac resident macrophages play a role in hypoxia-induced proliferation.
- This mechanism offers a novel therapeutic strategy for cardiovascular disease.
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.