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Published on: September 26, 2018
Hepatic Abnormal Secretion of Apolipoprotein C3 Promotes Inflammation in Aortic Dissection
Xinghui Zhuang1,2, Mohammad Zarif1,2, Yue Shen1,2
1Department of Cardiovascular Surgery Fujian Medical University Union Hospital Fuzhou China.
Insights
Abnormally secreted Apolipoprotein C3 (apo C3) from the liver promotes aortic dissection by driving inflammation and macrophage infiltration. Reducing hepatic apo C3 levels significantly decreased disease incidence in a mouse model.
Area of Science:
- Cardiovascular Biology
- Immunology
- Hepatology
Background:
- Apolipoprotein C3 (apo C3) is linked to sterile inflammation and organ damage.
- Elevated apo C3 is observed in plasma exosomes of patients with aortic dissection (AD).
- The specific role of apo C3 in AD pathogenesis is not well understood.
Purpose of the Study:
- To investigate the role of liver-derived apo C3 in the development of AD.
- To elucidate the mechanisms by which apo C3 influences AD progression.
- To explore apo C3's effects on aortic cells and macrophages.
Main Methods:
- Adeno-associated virus (AAV)-mediated knockdown of hepatic apo C3 in an AD mouse model.
- In vitro studies using recombinant apo C3 protein on J774A.1 macrophages.
- Assessment of apo C3's impact on aortic endothelial cells and vascular smooth muscle cells.
- Inhibition of the apo C3 receptor, Toll-like receptor 2 (TLR2).
Main Results:
- Hepatic apo C3 originates from abnormal liver secretion, enters circulation, and deposits in the aorta.
- AAV-mediated hepatic apo C3 knockdown significantly reduced AD incidence, macrophage infiltration, and aortic collagen deposition.
- Inhibition of TLR2 also significantly lowered AD incidence.
- In vitro, apo C3 promoted M1 macrophage polarization and matrix metalloproteinase secretion via TLR2/NLRP3 pathway activation.
- Apo C3 increased endothelial adhesion molecule expression and induced inflammation, chemotaxis, and apoptosis in vascular smooth muscle cells.
Conclusions:
- Abnormally secreted hepatic apo C3 plays a critical role in promoting aortic inflammation and AD.
- Targeting hepatic apo C3 secretion or its receptor TLR2 may offer therapeutic strategies for AD.
Background:
Apolipoprotein C3 (apo C3) is primarily secreted by the liver and is involved in promoting sterile inflammation and organ damage under pathological conditions. Previous studies have shown that apo C3 is abundant in the plasma exosomes of patients with aortic dissection (AD), but its specific role in AD remains unclear.
Methods And Results:
In vivo, adeno-associated virus was used to knock down hepatic apo C3 expression in an AD mouse model to assess the impact of liver-derived apo C3 on the development of AD. In vitro, recombinant apo C3 protein was added to the culture medium of J774A.1 macrophages to evaluate its effect on macrophage polarization and to identify the underlying mechanisms. Additionally, the effect of apo C3 on the function of aortic endothelial and smooth muscle cells was explored. Apo C3 in the aortas of AD mice was found to originate from abnormal hepatic secretion, which enters the bloodstream and subsequently deposits in the aorta. Adeno-associated virus-mediated hepatic apo C3 knockdown significantly reduced AD incidence (P=0.0036), macrophage infiltration (P=0.0004), and collagen deposition in the aorta (P=0.0016). Similarly, inhibiting the apo C3 receptor Toll-like receptor 2 significantly lowered AD incidence (P=0.0352). In vitro, recombinant apo C3 protein promoted M1 polarization and matrix metalloproteinase secretion in macrophages by activating the Toll-like receptor 2/NLR family pyrin domain containing 3 pathway. Additionally, apo C3 increased adhesion molecule expression in endothelial cells and induced inflammation, chemotaxis, and apoptosis in vascular smooth muscle cells.
Conclusions:
Our findings highlight the role of abnormally secreted hepatic apo C3 in promoting aortic inflammation.
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