Carboxyl-Terminal Modulator Protein Ameliorates Pathological Cardiac Hypertrophy by Suppressing the Protein Kinase B
Xiaoxiong Liu1,2,3, Qin Yang4,5,6,7, Li-Hua Zhu1
1Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.
Background:
Carboxyl-terminal modulator protein (CTMP) has been implicated in cancer, brain injury, and obesity. However, the role of CTMP in pathological cardiac hypertrophy has not been identified.
Methods And Results:
In this study, decreased expression of CTMP was observed in both human failing hearts and murine hypertrophied hearts. To further explore the potential involvement of CTMP in pathological cardiac hypertrophy, cardiac-specific CTMP knockout and overexpression mice were generated. In vivo experiments revealed that CTMP deficiency exacerbated the cardiac hypertrophy, fibrosis, and function induced by pressure overload, whereas CTMP overexpression alleviated the response to hypertrophic stimuli. Consistent with the in vivo results, adenovirus-mediated gain-of-function or loss-of-function experiments showed that CTMP also exerted a protective effect against hypertrophic responses to angiotensin II in vitro. Mechanistically, CTMP ameliorated pathological cardiac hypertrophy through the blockade of the protein kinase B signaling pathway. Moreover, inhibition of protein kinase B activation with LY294002 rescued the deteriorated effect in aortic banding-treated cardiac-specific CTMP knockout mice.
Conclusions:
Taken together, these findings imply, for the first time, that increasing the cardiac expression of CTMP may be a novel therapeutic strategy for pathological cardiac hypertrophy.
Insights
Carboxyl-terminal modulator protein (CTMP) protects against pathological cardiac hypertrophy. Increasing CTMP in the heart may offer a new therapeutic approach for this condition.
Area of Science:
- Cardiology
- Molecular Biology
- Biochemistry
Background:
- Carboxyl-terminal modulator protein (CTMP) is linked to various diseases, but its role in pathological cardiac hypertrophy is unknown.
- Decreased CTMP expression was found in human failing hearts and mouse hypertrophied hearts.
Purpose of the Study:
- To investigate the role of CTMP in pathological cardiac hypertrophy.
- To determine if CTMP has a protective effect against cardiac hypertrophy.
Main Methods:
- Generated cardiac-specific CTMP knockout and overexpression mouse models.
- Conducted in vivo pressure overload and in vitro angiotensin II stimulation experiments.
- Investigated the involvement of the protein kinase B (PKB) signaling pathway.
Main Results:
- CTMP deficiency worsened cardiac hypertrophy, fibrosis, and dysfunction in response to pressure overload.
- CTMP overexpression alleviated cardiac hypertrophy and improved function.
- CTMP protected against angiotensin II-induced hypertrophic responses in vitro.
- CTMP ameliorated cardiac hypertrophy by blocking the PKB signaling pathway.
- Inhibition of PKB activation rescued cardiac dysfunction in CTMP knockout mice.
Conclusions:
- CTMP plays a protective role in pathological cardiac hypertrophy.
- Increasing cardiac CTMP expression represents a potential novel therapeutic strategy for cardiac hypertrophy.
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