Loss of Smooth Muscle α-Actin Leads to NF-κB–Dependent Increased Sensitivity to Angiotensin II in Smooth Muscle Cells and Aortic Enlargement

Abstract

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.

Smooth muscle-specific Gsα deletion exaggerates angiotensin II-induced abdominal aortic aneurysm formation in mice in vivo

“…Here, we show that smooth muscle-specific Gsα deletion increased AAA formation by promoting the SMC phenotype switch, which was consistent with the mechanism found in smooth muscle-specific KLF4-knockout mice [14]. Another study directly demonstrated that loss of α-SMA increased the sensitivity to AngII by increasing Agtr1a level, which was established to drive AAA formation [40]. Thus, the SMC phenotype switch may be one of the most important mechanisms of AAA formation.…”

LTBP3 Pathogenic Variants Predispose Individuals to Thoracic Aortic Aneurysms and Dissections

“…We investigated these mice for cardiovascular pathology and identified significantly increased elastic lamellar units in Ltbp3 À/À ascending aortas compared to wild-type aortas, a finding that is also observed in another HTAD mouse model, Acta2 À/À mice (Figures 2A and 2B). 26,27 Similar to the Acta2 À/À mice, Ltbp3 À/À mice had reduced diastolic blood pressures in comparison to those of wild-type mice ( Figure 2C). 26,27 Previous studies reported that the diameters of the aortic root and ascending aorta of homozygous Ltbp3 À/À mice were similar to those of wild-type mice.…”

Toll-like receptor-4 signaling pathway in aorta aging and diseases: “its double nature”

“…In Chen, Madonna, Milewicz and colleagues, the role of genetic predisposition in the genesis of TAAs has been defined, and in particular it has been shown that loss of smooth muscle α-action leads to NF-κB-dependent increased susceptibility to Angiotensin II (Ang II) in smooth muscle cells and aortic enlargement [7]. In addition, we postulated a pattern of TAA onset, already defined by Ruvolo, Balistreri and colleagues [8] as double-face signal pathway model, given its features (see Fig.…”