Deficiency in Aim2 affects viability and calcification of vascular smooth muscle cells from murine aortas and Angiotensin-II induced aortic aneurysms

Abstract

Background: Phenotypic transformation of vascular smooth muscle cells is a key element in vascular remodeling and aortic aneurysm growth. Previously, deletion of several inflammasome components decreased formation of aortic aneurysm (AA) in the Angiotensin II (AngII) -induced mouse model. We hypothesized that the inflammasome sensor Absent in melanoma 2 (Aim2) might affect the phenotype of vascular smooth muscle cells (VSMC), thereby reducing AA formation. Methods : Aim2-/- mice and wild-type (WT) C57Bl/6J mice were used as an animal model. VSMC were isolated from 6 months old mice and grown in vitro . Young (passage 3-5) and senescent (passage 7-12) cells were analyzed in vitro for calcification in mineralization medium by Alizarin Red S staining. Expression of calcification and inflammatory markers were studied by real-time RT-PCR and Western blotting, release of cytokines was determined by ELISA. To induce AA, osmotic mini-pumps loaded with AngII (1500 ng/kg bodyweight/min) were implanted for 28 days in male mice at 6 months of age. Results : Compared with VSMC from WT mice, VSMC isolated from Aim2-/- mice were larger, less viable, and underwent stronger calcification in mineralization medium, along with induction of Bmp4 and repression of Tnfsf11/Rankl gene expression. In addition, Aim2 deficiency was associated with reduced inflammasome gene expression and release of Interleukin-6. Using the mouse model of AngII induced AA, Aim2 deficiency reduced AA incidence to 48.4% (15/31) in Aim2-/- mice versus 76.5% (13/17) in WT mice. In contrast to Aim2-/- mice, AA from WT mice expressed significantly increased levels of alpha-smooth muscle actin/ Acta2 , indicating tissue remodeling. Reduced cell proliferation in Aim2-/- mice was indicated by significantly increased p16ink4a/ Cdkn2a expression in untreated and AngII-infused aortas, and by significantly lower amounts of proliferating (Ki67 positive) VSMC in AngII-infused Aim2-/- mice. Conclusions: Our results suggest a role for Aim2 in regulating VSMC proliferation and transition to an osteoblast-like or osteoclast-like phenotype, thereby modulating the response of VSMC in aortic remodeling and AA Formation.

Collagen I is expressed by hepatocytes through activation of AIM2/ASC/caspase-1 signaling pathway

“…It was reported that AIM2 could inhibit the viability and increase the apoptosis rate of colorectal cancer (CRC) cells through suppressing the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway [33] . It was also reported that the de ciency of AIM2 could decrease the viability and calci cation of vascular smooth muscle cells from murine aortas [34] . The knockdown of AIM2 could result in reduction of viability in cutaneous cell carcinoma (cSCC) cells and onset of apoptosis [35] .…”

Possible effects of fibroblast growth factor 21 on vascular calcification via suppressing activating transcription factor 4 mediated apoptosis and osteogenic transformation in rats

“…As the final common pathway of VC, cell phenotype transformation is the ultimate cause of VC 30 . The overexpression of bone‐associated factors and decreased expression of contractile markers are associated with the phenotype transition of VSMCs from smooth muscle cell‐like phenotype to osteoblast‐like phenotype 31 .…”

“…As the final common pathway of VC, cell phenotype transformation is the ultimate cause of VC. 30 The overexpression of boneassociated factors and decreased expression of contractile markers are associated with the phenotype transition of VSMCs from smooth muscle cell-like phenotype to osteoblast-like phenotype. 31 Furthermore, because ATF4 is the bridge between ERS and VSMCs 32 In our research, for osteoblastic phenotype, ALP, a pro-biomarker of osteoblast-like differentiation, is activated before and persisting in VC.…”