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Ascending Aortic Constriction in Rats for Creation of Pressure Overload Cardiac Hypertrophy Model
Published on: June 29, 2014
C-C Motif Chemokine Receptor 9 Exacerbates Pressure Overload-Induced Cardiac Hypertrophy and Dysfunction
Zhengxi Xu1, Fanghua Mei2, Hanning Liu1
1State Key Laboratory of Cardiovascular Diseases, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
Insights
C-C motif chemokine receptor 9 (CCR9) drives pathological cardiac hypertrophy by activating the AKT-mTOR-GSK3β pathway. CCR9 deficiency protects against cardiac hypertrophy, highlighting its therapeutic potential for heart failure.
Area of Science:
- Cardiovascular Biology
- Immunology
- Molecular Medicine
Background:
- Maladaptive cardiac hypertrophy is a critical precursor to heart failure, a leading global cause of mortality.
- C-C motif chemokine receptor 9 (CCR9), a G protein-coupled receptor, is known for its role in immune cell regulation and immune-related diseases.
- Emerging evidence suggests CCR9 involvement in cardiovascular diseases, but its specific role in cardiac hypertrophy remains unclear.
Purpose of the Study:
- To investigate the role of C-C motif chemokine receptor 9 (CCR9) in the development of cardiac hypertrophy.
- To elucidate the underlying molecular mechanisms by which CCR9 influences pathological cardiac remodeling.
Main Methods:
- Assessed CCR9 protein levels in human failing hearts and experimental cardiac hypertrophy models.
- Utilized cardiac-specific CCR9 knockout and transgenic mice to perform loss- and gain-of-function studies under pressure overload.
- Examined signaling pathway activation, including mitogen-activated protein kinases (MAPKs) and AKT/protein kinase B, in response to altered CCR9 levels.
Main Results:
- CCR9 protein levels were significantly elevated in failing human hearts and experimental hypertrophy models.
- CCR9 deficiency attenuated pressure overload-induced cardiac hypertrophy, while CCR9 overexpression exacerbated it.
- CCR9 primarily modulated the AKT-mammalian target of rapamycin-glycogen synthase kinase 3β (AKT-mTOR-GSK3β) signaling cascade, not the MAPK pathway.
Conclusions:
- C-C motif chemokine receptor 9 (CCR9) plays a causal role in promoting pathological cardiac hypertrophy.
- The prohypertrophic effects of CCR9 are mediated through the AKT-mTOR-GSK3β signaling pathway.
- Targeting CCR9 may offer a novel therapeutic strategy for preventing or treating cardiac hypertrophy and subsequent heart failure.
Background:
Maladaptive cardiac hypertrophy is a major risk factor for heart failure, which is the leading cause of death worldwide. C-C motif chemokine receptor 9 (CCR9), a subfamily of the G protein-coupled receptor supergene family, has been highlighted as an immunologic regulator in the development and homing of immune cells and in immune-related diseases. Recently, CCR9 was found to be involved in the pathogenesis of other diseases such as cardiovascular diseases; however, the effects that CCR9 exerts in cardiac hypertrophy remain elusive.
Methods And Results:
We observed significantly increased CCR9 protein levels in failing human hearts and in a mouse or cardiomyocyte hypertrophy model. In loss- and gain-of-function experiments, we found that pressure overload-induced hypertrophy was greatly attenuated by CCR9 deficiency in cardiac-specific CCR9 knockout mice, whereas CCR9 overexpression in cardiac-specific transgenic mice strikingly enhanced cardiac hypertrophy. The prohypertrophic effects of CCR9 were also tested in vitro, and a similar phenomenon was observed. Consequently, we identified a causal role for CCR9 in pathological cardiac hypertrophy. Mechanistically, we revealed a lack of difference in the expression levels of mitogen-activated protein kinases between groups, whereas the phosphorylation of AKT/protein kinase B and downstream effectors significantly decreased in CCR9 knockout mice and increased in CCR9 transgenic mice after aortic binding surgery.
Conclusions:
The prohypertrophic effects of CCR9 were not attributable to the mitogen-activated protein kinase signaling pathway but rather to the AKT-mammalian target of rapamycin-glycogen synthase kinase 3β signaling cascade.
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