Licochalcone A attenuates abdominal aortic aneurysm induced by angiotensin II via regulating the miR‐181b/SIRT1/HO‐1 signaling

Abstract

Licochalcone A (LA), a chalcone derived from liquorice, exhibits multiple biological activities, including anti-oxidation and anti-inflammation. This study aimed to investigate the role and underlying mechanism of LA in the abdominal aortic aneurysm (AAA). AAA model was established by continuous infusion of 1000 ng/kg/min of angiotensin II (AngII) in ApoE -/mice for 4 weeks. At 7 days before AngII administration, 5 mg/kg/day or 10 mg/kg/day of LA was intraperitoneally administered to mice and continued for 4 weeks. The characteristics and quantification of AAAs were determined in situ. Real-time PCR or western blot was used to measure mRNA or protein levels of matrix metalloproteinase 2 and matrix metalloproteinase 9; pro-inflammatory cytokines tumor necrosis factor-α, interleukin-1β, and interleukin-6; apoptosis-related proteins Bax, Bcl-2, and active caspase-3; miR-181b; Sirtuin 1 (SIRT1); and heme oxygenase-1 (HO-1). Mouse-aorta-origin vascular smooth muscle (MOVAS) cells were used to confirm the involved pathways in vitro. We found LA administration dose-dependently reduced the incidence of AngII-induced AAA, aneurysm diameter enlargement, elastin degradation, matrix metalloproteinase production, pro-inflammatory cytokines and miR-181b expression, and vascular smooth muscle cell apoptosis. It elevated SIRT1 and HO-1 expression that was suppressed by AngII.AngII enhanced miR-181b but reduced SIRT1 and HO-1 expression in MOVAS cells. In AngII-stimulated MOVAS cells, downregulation of miR-181b significantly upregulated the expression of SIRT1 and HO-1, the effect of which was abrogated by SIRT1 siRNA.Collectively, LA could attenuate AngII-induced AAA by modulating the miR-181b/ SIRT1/HO-1 signaling. LA might be a potential medical therapy for small AAA. K E Y W O R D S abdominal aortic aneurysm (AAA), angiotensin II, licochalcone A (LA), miR-181b, SIRT1/HO-1

Histone Deacetylase SIRT1, Smooth Muscle Cell Function, and Vascular Diseases

“…However, the beneficial effect of CR on the development of AAAs was abolished in VSMC-specific SIRT1 knockout mice (Liu et al, 2016). Additionally, Licochalcone A (LA), a component derived from liquorice, attenuated Ang IIinduced AAA formation in apoE −/− mice, which also required SIRT1 up regulation in VSMCs (Hou et al, 2019). Besides AAAs, SIRT1 is also important in the prevention of thoracic aortic aneurysm/dissection (TAAD).…”

The Role of Sirtuin-1 in the Vasculature: Focus on Aortic Aneurysm

“…These interactions suggest that positive feedback mechanisms between SirT1 and HO-1 might be at play in the vasculature, and they may affect HO-1mediated cytoprotection in cardiovascular diseases. To this end, pharmacological activation of miR-181b/SirT1/HO-1 signaling axis reduced the development of ang II-induced AAA in apoE-/-mice (Hou et al, 2019). Although the exact molecular mechanisms accounting for the interaction between SirT-1 and HO-1, and its functional significance in vascular pathology, remain to be fully elucidated, the development of specific targeted therapies that modulate the SirT1/HO-1 axis could represent a new therapeutic strategy for the management of AA disease, as well as other vascular diseases.…”

“…Thus far, numerous plant-derived molecules have shown promising results, although proving their pharmacological specificity remains a challenge. Liquorice-derived licochalcone attenuates angII-induced AAA by modulating the miR-181b/SirT1/HO-1 signaling axis (Hou et al, 2019). Resveratrol, a grape-derived non-toxic polyphenol known to activate SirT1, decreases the incidence of AAA in angII-infused apoE −/− mice fed a high fat diet by increasing ACE2 and downregulating NF-kB, Akt, ERK1/2 and ATR1 in human aortic VSM (Moran et al, 2017).…”

“…Sirtuin-1 (SirT1, mammalian homolog of silent information regulator (Sir2) in yeast) is a nicotinamide adenine dinucleotide (NAD + )-dependent class III histone deacetylase (Frye, 2000) and the best characterized member of the sirtuins family in mammalians (Haigis and Sinclair, 2010). Compelling evidence have demonstrated beneficial effects of SirT1 in the cardiovascular system, generally attributed to anti-oxidant (Kawai et al, 2011;Zhou et al, 2011), anti-senescence (Ota et al, 2010a;Thompson et al, 2014;Chen et al, 2016), anti-apoptotic (Hibender et al, 2016;Hou et al, 2019), and anti-inflammatory effects (Sosnowska et al, 2017;D'Onofrio et al, 2018). In the vasculature, SirT1 is expressed in the endothelium, vascular smooth muscle (VSM) and adventitia (Potente et al, 2007;Miyazaki et al, 2008;Li et al, 2011;Fry et al, 2015;Chen et al, 2016;Ling et al, 2017).…”

Fengbaisan suppresses endoplasmic reticulum stress by up-regulating SIRT1 expression to protect rats with chronic obstructive pulmonary diseases

“…Salviae miltiorrhizae exerts anti-inflammatory effects by regulating SIRT1/NF-jB signalling pathway (Liu et al 2019). Licochalcone A exerts antioxidant and anti-inflammatory effects by up-regulating SIRT1 expression (Hou et al 2019). Therefore, we established a COPD rat model to clarify whether Fengbaisan could inhibit ERS by up-regulating SIRT1 expression and improve COPD.…”