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Published on: September 26, 2018
ClC-3 deficiency prevents atherosclerotic lesion development in ApoE-/- mice
Jing Tao1, Can-Zhao Liu2, Jing Yang2
1Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China; Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou 215006, China.
Background:
Recent evidence suggested that ClC-3, encoding Cl(-) channel or Cl(-)/H(+) antiporter, plays a critical role in regulation of a variety of physiological functions. However, remarkably little is known about whether ClC-3 is involved in atherosclerosis. This study aims to establish the involvement and direct role of ClC-3 in atherogenesis and underlying mechanisms by using ClC-3 and ApoE double null mice.
Methods And Results:
After a 16-week western-type high-fat diet, the ClC-3(+/+)ApoE(-/-) mice developed widespread atherosclerotic lesions in aorta. However, the lesion size was significantly reduced in aorta of ClC-3(-/-)ApoE(-/-) mice. Compared with the ClC-3(+/+) controls, there was significantly decreased ox-LDL binding and uptake in isolated peritoneal macrophages from ClC-3(-/-) mice. Moreover, the expression of scavenger receptor SR-A, but not CD36, was significantly decreased in both ClC-3(-/-) peritoneal macrophages and aortic lesions from ClC-3(-/-)ApoE(-/-) mice. These findings were further confirmed in ox-LDL-treated RAW264.7 macrophages, which showed that silence of ClC-3 inhibited SR-A expression, ox-LDL accumulation and foam cell formation, whereas overexpression of ClC-3 produced the opposite effects. In addition, ClC-3 siRNA significantly inhibited, whereas ClC-3 overexpression increased, the phosphorylation of JNK/p38 MAPK in ox-LDL-treated RAW264.7 foam cells. Pretreatment with JNK or p38 inhibitor abolished ClC-3-induced increase in SR-A expression and ox-LDL uptake. Finally, the increased JNK/p38 phosphorylation and SR-A expression induced by ClC-3 could be mimicked by reduction of [Cl(-)]i by low Cl(-) solution.
Conclusions:
Our findings demonstrated that ClC-3 deficiency inhibits atherosclerotic lesion development, possibly via suppression of JNK/p38 MAPK dependent SR-A expression and foam cell formation.
Insights
Chloride channel 3 (ClC-3) deficiency reduces atherosclerosis development by suppressing scavenger receptor A (SR-A) expression and foam cell formation. This involves the JNK/p38 MAPK pathway, highlighting ClC-3 as a potential therapeutic target for atherosclerosis.
Area of Science:
- Molecular Biology
- Cardiovascular Research
- Ion Channel Function
Background:
- Chloride channel 3 (ClC-3) is implicated in various physiological processes.
- Its role in atherosclerosis, a complex cardiovascular disease, remains largely unexplored.
- This study investigates the direct involvement of ClC-3 in atherogenesis.
Purpose of the Study:
- To elucidate the role of ClC-3 in the development of atherosclerosis.
- To investigate the underlying molecular mechanisms connecting ClC-3 to atherogenesis.
- To utilize a double knockout mouse model (ClC-3 and ApoE) for comprehensive analysis.
Main Methods:
- Utilized ClC-3 and Apolipoprotein E (ApoE) double knockout mice fed a high-fat diet.
- Assessed atherosclerotic lesion size in the aorta.
- Analyzed oxidized low-density lipoprotein (ox-LDL) binding and uptake in macrophages.
- Investigated the expression of scavenger receptor A (SR-A) and CD36.
- Utilized cell culture models (RAW264.7 macrophages) with ClC-3 knockdown or overexpression.
- Examined the phosphorylation status of JNK/p38 MAPK signaling pathway.
- Tested the effect of ClC-3 on intracellular chloride concentration ([Cl(-)]i).
Main Results:
- ClC-3 deficiency significantly reduced atherosclerotic lesion size in ApoE knockout mice.
- Macrophages from ClC-3 deficient mice showed decreased ox-LDL uptake and reduced SR-A expression.
- ClC-3 deficiency suppressed JNK/p38 MAPK phosphorylation, SR-A expression, and foam cell formation in macrophages.
- Reduced intracellular chloride mimicked the effects of ClC-3 deficiency on SR-A expression and MAPK signaling.
Conclusions:
- ClC-3 deficiency confers protection against atherosclerotic lesion development.
- The protective effect is mediated by the suppression of JNK/p38 MAPK-dependent SR-A expression and foam cell formation.
- ClC-3 emerges as a potential therapeutic target for mitigating atherosclerosis.
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