ABSTRACT
Aortic aneurysm and dissection (AAD) are severe vascular diseases with high mortality rates. However, the causal relationship between serum uric acid levels and the occurrence of AAD remains a subject of controversy. To address this issue, we conducted a two-sample Mendelian randomization (MR) analysis to investigate whether there is a causal association between these factors. We obtained single-nucleotide polymorphisms (SNPs) data related to serum uric acid levels from the FinnGen study and data on AAD from the UK Biobank. Various two-sample MR methods, including inverse variance weighted (IVW) analysis, MR-Egger regression analysis, weighted median analysis, and contamination mixture method, were employed to assess the causal relationship between serum uric acid and the risk of AAD. Sensitivity analysis was conducted to evaluate the stability and reliability of the results. The findings revealed a positive association between serum uric acid levels and the risk of aortic aneurysm (AA) (odds ratio [OR] = 1.200, 95 % confidence interval [CI]: 1.020-1.400, P = 0.0239). However, no significant correlation was observed between serum uric acid levels and the occurrence of aortic dissection (AD) (OR = 0.893, 95 % CI = 0.602-1.326, P = 0.576). Our study, which employed MR analysis, identified a positive association between serum uric acid levels and the risk of AA. However, we did not observe a significant correlation with AD.
ABSTRACT
BACKGROUND: Vascular calcification (VC) is an independent risk factor for cardiovascular diseases. Recently, ferroptosis has been recognised as a novel therapeutic target for cardiovascular diseases. Although an association between ferroptosis and vascular calcification has been reported, the role and mechanism of iron overload in vascular calcification are still poorly understood. Specifically, further in-depth research is required on whether metalloproteins SLC39a14 and SLC39a8 are involved in ferroptosis induced by iron overload. METHODS: R language was employed for the differential analysis of the dataset, revealing the correlation between ferroptosis and calcification. The experimental approaches encompassed both in vitro and in vivo studies, incorporating the use of iron chelators and models of iron overload. Additionally, gain- and loss-of-function experiments were conducted to investigate iron's effects on vascular calcification comprehensively. Electron microscopy, immunofluorescence, western blotting, and real-time polymerase chain reaction were used to elucidate how Slc39a14 and Slc39a8 mediate iron overload and promote calcification. RESULTS: Ferroptosis was observed in conjunction with vascular calcification (VC); the association was consistently confirmed by in vitro and in vivo studies. Our results showed a positive correlation between iron overload in VSMCs and calcification. Iron chelators are effective in reversing VC and iron overload exacerbates this process. The expression levels of the metal transport proteins Slc39a14 and Slc39a8 were significantly upregulated during calcification; the inhibition of their expression alleviated VC. Conversely, Slc39a14 overexpression exacerbates calcification and promotes intracellular iron accumulation in VSMCs. CONCLUSIONS: Our research demonstrates that iron overload occurs during VC, and that inhibition of Slc39a14 and Slc39a8 significantly relieves VC by intercepting iron overload-induced ferroptosis in VSMCs, providing new insights into the VC treatment.
