Role of the mTOR Signalling Pathway in Experimental Rabbit Vein Grafts
Qun Wang1, Li Wan1, Liqiao Liu2
1Department of Cardiovascular Surgery, Cardiovascular Research Institute Laboratory, First Hospital of Nanchang University, Nanchang 330000, China.
Background:
Coronary artery bypass grafting is employed for the treatment of multiple-vessel lesions. Studies have shown that continued maladaptive remodelling expedites atherosclerosis and that excessive remodelling leads to graft restenosis. However, few studies have focussed on mechanistic target of rapamycin (mTOR) signalling involved during remodelling of transplanted veins.
Methods:
Rabbits were randomly allocated to groups undergoing vein-graft restenosis or sham surgery. At 1, 3, 7, 14, 28 and 90 days after surgery, we removed bypassed grafts and placed them in groups named T1, T2, T3, T4, T5 and T6, respectively. Group T0 denoted the control group. Analysis included vessel thickness, electron microscope data, TUNEL staining, and expression of the proliferation-associated gene proliferating cell nuclear antigen (PCNA). We chose specific time-points of gene expression, and then observed changes in the mTOR signalling.
Results:
The early stage of vein grafting (one to three days after surgery) led to apoptosis and degradation of the extracellular matrix. Seven days after surgery, cells began to proliferate. RICTOR expression in mTOR complex 2 (mTORC2) and that of its downstream substrate protein kinase C was enhanced in the early stage (T1 and T3), and was higher in T1. mTORC1's upstream gene regulation decreased in T1 and increased in T3. Its downstream genes eIF4b and 4E-BP showed similar changes. Expression of eIF4e and eIF4b increased, and led to an increase in protein composition.
Conclusions:
After transplantation, mTORC1 function and its upstream and downstream genes were inhibited on the first day after grafting, but mTORC2 function was enhanced. One week after surgery, mTORC2 was still overexpressed when mTORC1 function had recovered and became enhanced. Hence, mTORC2 plays a major role in arterialisation of veins.
Insights
Mechanistic target of rapamycin (mTOR) signaling in vein grafts shows early inhibition of mTORC1 and enhanced mTORC2 function. mTORC2 plays a key role in vein arterialization following transplantation.
Area of Science:
- Vascular biology
- Cardiovascular surgery
- Molecular signaling
Background:
- Coronary artery bypass grafting treats multiple-vessel lesions.
- Vein graft remodeling can lead to atherosclerosis and restenosis.
- Mechanistic target of rapamycin (mTOR) signaling in vein graft remodeling is understudied.
Purpose of the Study:
- To investigate the role of mechanistic target of rapamycin (mTOR) signaling in vein graft remodeling.
- To elucidate the involvement of mTOR complexes in the arterialization process of transplanted veins.
Main Methods:
- Rabbit models of vein-graft restenosis and sham surgery were used.
- Grafts were analyzed at multiple time points (1-90 days) for vessel thickness, ultrastructure, apoptosis, and proliferation (PCNA).
- Expression and activity of mTORC1 and mTORC2 signaling pathways were assessed.
Main Results:
- Early vein grafting (1-3 days) induced apoptosis and extracellular matrix degradation.
- Cell proliferation began around 7 days post-surgery.
- mTORC2 (RICTOR) and its substrate PKC were enhanced early, while mTORC1 activity was initially inhibited then recovered and enhanced by day 7.
Conclusions:
- mTORC1 function is inhibited early post-transplantation, whereas mTORC2 function is enhanced.
- mTORC2 remains overexpressed one week after surgery when mTORC1 function recovers.
- mTORC2 plays a significant role in the arterialization of veins after grafting.
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