RESUMO
BACKGROUND: Vascular calcification, which is characterized by calcium deposition in arterial walls and the osteochondrogenic differentiation of vascular smooth muscle cells, is an actively regulated process that involves complex mechanisms. Vascular calcification is associated with increased cardiovascular adverse events. The role of 4-hydroxynonenal (4-HNE), which is the most abundant stable product of lipid peroxidation, in vascular calcification has been poorly investigated. METHODS: Serum was collected from patients with chronic kidney disease and controls, and the levels of 4-HNE and 8-iso-prostaglandin F2α were measured. Sections of coronary atherosclerotic plaques from donors were immunostained to analyze calcium deposition and 4-HNE. A total of 658 patients with coronary artery disease who received coronary computed tomography angiography were recruited to analyze the relationship between coronary calcification and the rs671 mutation in aldehyde dehydrogenase 2 (ALDH2). ALDH2 knockout (ALDH2-/-) mice, smooth muscle cell-specific ALDH2 knockout mice, ALDH2 transgenic mice, and their controls were used to establish vascular calcification models. Primary mouse aortic smooth muscle cells and human aortic smooth muscle cells were exposed to medium containing ß-glycerophosphate and CaCl2 to investigate cell calcification and the underlying molecular mechanisms. RESULTS: Elevated 4-HNE levels were observed in the serum of patients with chronic kidney disease and model mice and were detected in calcified artery sections by immunostaining. ALDH2 knockout or smooth muscle cell-specific ALDH2 knockout accelerated the development of vascular calcification in model mice, whereas overexpression or activation prevented mouse vascular calcification and the osteochondrogenic differentiation of vascular smooth muscle cells. In patients with coronary artery disease, patients with ALDH2 rs671 gene mutation developed more severe coronary calcification. 4-HNE promoted calcification of both mouse aortic smooth muscle cells and human aortic smooth muscle cells and their osteochondrogenic differentiation in vitro. 4-HNE increased the level of Runx2 (runt-related transcription factor-2), and the effect of 4-HNE on promoting vascular smooth muscle cell calcification was ablated when Runx2 was knocked down. Mutation of Runx2 at lysine 176 reduced its carbonylation and eliminated the 4-HNE-induced upregulation of Runx2. CONCLUSIONS: Our results suggest that 4-HNE increases Runx2 stabilization by directly carbonylating its K176 site and promotes vascular calcification. ALDH2 might be a potential target for the treatment of vascular calcification.
Assuntos
Aldeído-Desidrogenase Mitocondrial , Aldeídos , Subunidade alfa 1 de Fator de Ligação ao Core , Camundongos Knockout , Miócitos de Músculo Liso , Calcificação Vascular , Animais , Aldeídos/metabolismo , Calcificação Vascular/metabolismo , Calcificação Vascular/genética , Calcificação Vascular/patologia , Humanos , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Aldeído-Desidrogenase Mitocondrial/genética , Aldeído-Desidrogenase Mitocondrial/metabolismo , Camundongos , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Masculino , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Feminino , Pessoa de Meia-Idade , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/patologia , Células Cultivadas , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/patologia , IdosoRESUMO
BACKGROUND: It is uncertain how COVID-19 outbreak influences the hepatitis B epidemics. This study aims to evaluate the effects on hepatitis B owing to the COVID-19 outbreak and forecast the hepatitis B epidemiological trend in mainland China to speed up the course of the "End viral hepatitis Strategy". METHODS: We estimated the causal impacts and created a forecast through adopting monthly notifications of hepatitis B each year from 2005 to 2020 in mainland China using the Bayesian structural time series (BSTS) method. RESULTS: The hepatitis B epidemics fluctuates irregularly during the period 2005-2007(APC = 8.7, P = 0.246) and 2015-2020(APC = 1.7, P = 0.290), and there is a downturn (APC=-3.2, 95% CI -5.2 to -1.2, P = 0.006) from 2007 to 2015 in mainland China. The COVID-19 outbreak was found to have a monthly average reduction on the hepatitis B epidemics of 26% (95% CI 18-35%) within the first three months in 2020,17% (95% CI 7.7-26%) within the first six months in 2020, and 10% (95% CI19-22%) all year as a result of the COVID-19 outbreak, (probability of causal effect = 96.591%, P = 0.034) and the forecasts showed an upward trend from 2021 to 2025 (annual percentage change = 4.18, 95% CI 4.0 to 4.3, P < 0.001). CONCLUSION: The COVID-19 has a positive effect on the decline of hepatitis B cases. And the potential of BSTS model to forecast the epidemiological trend of the hepatitis B can be applied in automatic public health policymaking in mainland China.