Downregulation of Filamin a Expression in the Aorta Is Correlated With Aortic Dissection

Abstract

Filamins (FLNs) are actin cross-linking proteins, and as scaffolding proteins, FLNs are closely associated with the stabilization of the cytoskeleton. Nevertheless, the biological importance of FLNs in aortic dissection (AD) has not been well-elucidated. In this study, we first reanalyzed datasets downloaded from the Gene Expression Omnibus (GEO) database, and we found that in addition to the extracellular matrix, the actin cytoskeleton is a key structure associated with AD. Given that FLNs are involved in remodeling the cytoskeleton to affect cellular functions, we measured their expression levels in the aortas of patients with Stanford type A AD (TAAD). Our results showed that the mRNA and protein levels of FLNA were consistently decreased in dissected aortas of both humans and mice, while the FLNB protein level was upregulated despite decreased FLNB mRNA levels, and comparable expression levels of FLNC were observed between groups. Furthermore, the immunohistochemistry results demonstrated that FLNA was highly expressed in smooth muscle cells (SMCs) of aorta in non-AD samples, and downregulated in the medial layer of the dissected aortas of humans and mice. Moreover, we revealed that FOS and JUN, forming a dimeric transcription factor called AP-1 (activating protein-1), were positively correlated with the expression of FLNA in aorta. Either overexpression of FOS or JUN alone, or overexpression of FOS and JUN together, facilitated the expression of FLNA in primary cultured human aortic SMCs. In the present study, we not only detected the expression pattern of FLNs in aortas of humans and mice with or without AD, but we also found that the expression of FLNA in the AD samples was significantly reduced and that AP-1 might regulate the expression of FLNA. Our findings will contribute to the elucidation of the pathological mechanisms of AD and provide potential therapeutic targets for AD.

β-Aminopropionitrile-induced aortic aneurysm and dissection in mice

“…The loss of smooth muscle cells (SMCs) in BAPN-induced AAD has been attributed to apoptosis ( Fig 1 ). 52 , 54 , 55 , 54 , 55 , 56 Consistent with the promotion of SMC apoptosis, AKT phosphorylation was downregulated in mice after BAPN administration. 52 , 60 , 79 However, phosphorylation of ERK is controversial in the BAPN-induced AAD mouse model.…”

“…After 28 days of BAPN administration, the accumulation of leukocytes at the site of medial rupture and the surrounding adventitia was evident. 45 , 46 , 47 , 48 , 49 , 53 , 54 , 55 , 56 , 79 For mice surviving 4 weeks of BAPN administration, thrombi had resolved; however, continuous leukocyte infiltration and disorganized collagen deposition were still prominent. After prolonged administration of BAPN for ≤12 weeks, 47 , 48 pronounced thinning of the aortic wall in the ascending and descending thoracic aortic regions was observed.…”

“…The rate of death from aortic rupture has been reported to be ~ 50% to 80%. 12 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 63 , 64 , 79 …”

Comprehensive Analysis of Key m6A Modification Related Genes and Immune Infiltrates in Human Aortic Dissection

“…The TGF-β signaling is linked to the pathogenesis of CVDs like AS and cardiac fibrosis ( 39 ). An experiment has verified that FLNA is highly expressed in SMCs of aorta in non-AD samples, but down-regulated in the medial layer of the dissected aortas ( 40 ). Consistently, our bioinformatics research also came to the same result that FLNA was a down-regulated gene of AD.…”

JIB-04, a histone demethylase Jumonji C domain inhibitor, regulates phenotypic switching of vascular smooth muscle cells

“…H&E staining was performed to observe whether the thickness of the intima layer was increased in the injured carotid artery. Immunohistochemistry assays were performed as described previously [ 39 ]. Briefly, tissue slices were first deparaffined with xylene and hydrated with gradient ethanol.…”