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. 2021 Sep 6;9(9):1171. doi: 10.3390/biomedicines9091171

Table 1.

Impact of various antioxidant therapies on aneurysm development in MFS.

Type of Therapy Type of Study Important Results Ref.
Resveratrol (Res) Animal study
Adult male Wistar rats fed with HFS diet in the presence or absence of Res for 3 months.
Cultured BAECs
Res protected against HFS- or high-glucose-induced increase in NADPH oxidase p47phox expression and decrease in SIRT1 level.
Conclusion: Res can reverse the senescence process in the aorta induced by HFS in rats or by exposure to high glucose in cultured BAECs. The underlying mechanism is SIRT1/NADPH oxidase pathway-dependent.
[122]
Animal study
Fbn1 (C1039G/+) MFS mouse model.
Cultured SMC
Resveratrol enhanced the nuclear localization of sirtuin-1 in the vessel wall.
It had no effect on leukocyte infiltration, activation of SMAD2 and ERK1/2.
Resveratrol reduced aortic elastin breaks and decreased micro-RNA-29b expression.
Resveratrol’s effect on micro-RNA-29b downregulation was endothelial cell- and nuclear factor κB-dependent.
[115]
Animal study
Male Sprague-Dawley rats on Resveratrol (10 mg/kg/die) or vehicle (Et-OH) alone for 7 days before until 14 days after the AAA induction with elastase
Resveratrol counteracted the CD62L-monocyte subset expansion, CD143 monocyte expression and circulating levels of MMP-9 activity and TNFα associated with AAA induction.
Resveratrol markedly attenuated AAA expansion, vessel wall macrophage infiltration and MMP-9, VEGF and TNFα expression, compared with AAA from Et-OH group.
Conclusions: Resveratrol limited the monocyte-dependent inflammatory response, macrophage differentiation and aortic lumen enlargement in elastase-induced AAA.
[124]
Animal study
Fibrillin-1 hypomorphic mice; Fbn1mgR/mgR receiving resveratrol (105 mg/kg/day mixed in food)
The addition of resveratrol to food significantly reduced mortality of Fbn1mgR/mgR mice compared to mice on regular chow.
Resveratrol-fed mice had considerably decreased plasma levels of active TGF-β1 and higher levels of total reversible oxidations of proteins compared to wild-type mice.
Conclusions: Resveratrol may diminish the incidence and mortality of aortic aneurysm via reduction of oxidative post-translational modifications of SirT-1 in VSM cells and inhibition of excessive TGF-β1 in Fbn1mgR/mgR mice.
[121]
Targeted therapies inducing HO-1: heme, rosuvastatin Porcine pancreatic elastase (PPE) model of AAA induction in HO-1 heterozygous (HO-1+/−, HO-1 Het) mice (heme).
Murine AAA model (Ang II-ApoE−/−) (resveratrol)
Deficiency in HO-1 leads to augmented AAA development.
Peritoneal macrophages from HO-1+/− mice showed increased gene expression of MCP-1, TNF-alpha, IL-1-beta and IL-6, and decreased expression of anti-inflammatory cytokines (IL-10 and TGF-β).
Treatment with heme returned AAA progression in HO-1 Het mice to a wild-type profile.
Low doses of rosuvastatin can induce HO-1 expression in aortic tissue and suppress AAA progression.
Conclusions: Pleiotropic statin effects might be beneficial in AAA, possibly through the upregulation of HO-1.
[128]
n-3 PUFA docosahexaenoic acid (DHA) Cells obtained from men with small AAA and age-matched male controls incubated with DHA for 1 h before exposure to 0.1 µg/mL LPS for 24 h DHA supplementation decreased the concentration of TNF-α and IL-6 in macrophage supernatants.
DHA increased glutathione peroxidase activity and HO-1 mRNA expression.
[130]
Lipoic acid
Losartan
MFS mgΔloxPneo mouse model vs. WT mice: untreated, treated with losartan and treated with lipoic acid MFS animals treated with lipoic acid showed markedly reduced ROS production and lower ERK1/2 phosphorylation.
Aortic dilation and elastic fiber breakdown were unaltered.
Absence of focal inhomogeneous regions in MFS animals treated with lipoic acid.
Losartan reduced aortic dilation and elastic fiber breakdown despite no change in ROS generation.
[132]
Hibiscus sabdariffa Linne HSL infusion in MFS patients Treatment significantly decreased ECSOD (p = 0.03), EGPx (p = 0.04), GST (p = 0.03), GSH (p = 0.01) and TAC and ascorbic acid (p = 0.02).
GSSG-R activity (p = 0.04) and LPO (p = 0.02) were increased in MFS patients vs. patients receiving the HSL.
Conclusions: Infusion of HSL allows an increase in antioxidant capacity of both the enzymatic and nonenzymatic systems, in the plasma of the MSF patients.
[137]
Losartan MFS mice lacking ATR1a expression MFS/ATR1a-null mice showed unabated aortic root enlargement and remained fully responsive to losartan.
Losartan’s anti-remodeling properties may be ATR- independent.
Losartan can activate the endothelial function in mice and patients.
In vitro, losartan can increase endothelial NO release in the absence of AngII and correct MFS NO levels in vivo.
Conclusions: Increased protective endothelial function, rather than ATR1 inhibition or BP lowering, may be beneficial in preventing aortic root disease in MFS.
[159]
Sub-BP-lowering dose valsartan
Hypotensive dose of losartan
Patients with MFS Valsartan attenuated MFS aortic root widening by 75.9%.
A similar effect was seen in the case of a hypotensive dose of losartan (79.4%).
Medial thickening, elastic fiber fragmentation and phospho-ERK signaling were inhibited to a similar degree with both treatments.
Valsartan and losartan decreased vascular contractility ex vivo in a NO-sensitive fashion.
Conclusions: Artic root stability can be achieved with valsartan in absence of BP-lowering effects.
[160]

BAECs—bovine aortic endothelial cells; BP—blood pressure; ERK1/2—extracellular signal-regulated kinase 1/2; Et-OH—ethanol; HFS—high-fat/sucrose; HO-1—heme oxygenase-1; IL-6—interleukin-6; LPS—lipopolysaccharide; SMC—smooth muscle cells; TNF-α—tumor necrosis factor-α; WT—wild-type.