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BACKGROUND

Vascular calcification is a detrimental aging pathology markedly accelerated in patients with chronic kidney disease. PLA (prelamin A) is a biomarker of vascular smooth muscle cell aging that accelerates calcification however the mechanisms remain undefined.

METHODS

Vascular smooth muscle cells were transduced with PLA using an adenoviral vector and epigenetic modifications were monitored using immunofluorescence and targeted polymerase chain reaction array. Epigenetic findings were verified in vivo using immunohistochemistry in human vessels, in a mouse model of inducible prelamin A expression, and in a rat model of chronic kidney disease-induced calcification. Transcriptomic and chromatin immunoprecipitation followed by sequencing analyses were used to identify gene targets impacted by changes in the epigenetic landscape. Molecular tools and antibody arrays were used to monitor the effects of mineral dysregulation on heterochromatin, inflammation, aging, and calcification.

RESULTS

Here, we report that depletion of the repressive heterochromatin marks, H3K9me3 (histone H3, lysine 9, trimethylation) and H3K27me3 (histone H3, lysine 27,trimethylation), is an early hallmark of vascular aging induced by both nuclear lamina dysfunction and dysregulated mineral metabolism, which act to modulate the expression of key epigenetic writers and erasers. Global analysis of H3K9me3 and H3K27me3 marks and pathway analysis revealed deregulation of insulin signaling and autophagy pathways as well as cross-talking DNA damage and NF-κB (nuclear factor κB) inflammatory pathways consistent with early activation of the senescence-associated secretory phenotype. Expression of PLA in vivo induced loss of heterochromatin and promoted inflammation and osteogenic differentiation which preceded aging indices, such as DNA damage and senescence. Vessels from children on dialysis and rats with chronic kidney disease showed prelamin A accumulation and accelerated loss of heterochromatin before the onset of calcification.

CONCLUSIONS

Dysregulated mineral metabolism drives changes in the epigenetic landscape and nuclear lamina dysfunction that together promote early induction of inflammaging pathways priming the vasculature for downstream pathological change.

BACKGROUND

METHODS

RESULTS

CONCLUSIONS

背景

血管钙化是一种有害的衰老病理过程，在慢性肾脏病患者中显著加速。前层蛋白A（prelamin A）是血管平滑肌细胞衰老的生物标志物，可加速钙化，但其机制尚不清楚。

方法

使用腺病毒载体将前层蛋白A转导至血管平滑肌细胞，并通过免疫荧光和靶向聚合酶链反应阵列监测表观遗传修饰。在人体血管、诱导性前层蛋白A表达的小鼠模型以及慢性肾脏病诱导钙化的大鼠模型中，通过免疫组织化学在体内验证表观遗传学发现。采用转录组学和染色质免疫沉淀测序分析来鉴定受表观遗传格局变化影响的基因靶点。使用分子工具和抗体阵列监测矿物质失调对异染色质、炎症、衰老和钙化的影响。

结果

在此，我们报告抑制性异染色质标记H3K9me3（组蛋白H3赖氨酸9三甲基化）和H3K27me3（组蛋白H3赖氨酸27三甲基化）的缺失是由核纤层功能障碍和矿物质代谢失调诱导的血管衰老的早期标志，它们作用于调节关键表观遗传书写因子和擦除因子的表达。对H3K9me3和H3K27me3标记的全局分析以及通路分析显示胰岛素信号通路和自噬通路失调，以及与衰老相关分泌表型的早期激活一致的DNA损伤和核因子κB（NF-κB）炎症通路的相互作用。体内前层蛋白A的表达导致异染色质丢失，并促进炎症和成骨分化，这先于衰老指标，如DNA损伤和衰老。接受透析的儿童以及患有慢性肾脏病的大鼠的血管在钙化开始前显示前层蛋白A积累和异染色质加速丢失。