Loss of Smooth Muscle α-actin Leads to NF-κB-Dependent Increased Sensitivity to Angiontensin II in Smooth Muscle Cells and Aortic Enlargement
Rationale: Mutations in ACTA2, encoding the smooth muscle isoform of α-actin (SM α-actin), cause thoracic aortic aneurysms, acute aortic dissections, and occlusive vascular diseases.
Objective: We sought to identify the mechanism by which loss of SM α-actin causes aortic disease.
Methods and Results: Acta2-/- mice have an increased number of elastic lamellae in the ascending aorta and progressive aortic root dilation as assessed by echocardiography that can be attenuated by treatment with losartan, an angiotensin II (AngII) type 1 receptor blocker. AngII levels are not increased in Acta2-/- aortas or kidneys. Aortic tissue and explanted smooth muscle cells (SMCs) from Acta2-/- aortas show increased production of reactive oxygen radicals (ROS) and increased basal NF-κB signaling, leading to an increase in the expression of the AngII receptor type I (Agtr1a) and activation of signaling at 100-fold lower levels of AngII in the mutant compared to wild-type cells. Furthermore, disruption of SM α-actin filaments in wildtype SMCs by various mechanisms activates NF-κB signaling and increases expression of Agtr1a.
Conclusions: These findings reveal that disruption of SM α-actin filaments in SMCs increases ROS levels, activates NF-κB signaling and increases Agtr1a expression, thus potentiating AngII signaling in vascular SMCs without an increase in the exogenous levels of AngII.
- Received January 2, 2017.
- Revision received April 24, 2017.
- Accepted May 1, 2017.