Transcriptional analysis reveals that the intracellular lipid accumulation impairs gene expression profiles involved in insulin response-associated cardiac functionality.
Transcriptional analysis reveals that the intracellular lipid accumulation impairs gene expression profiles involved in insulin response-associated cardiac functionality.
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DOI：
10.1038/s41598-023-35951-6
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发表时间：
2023-05-30
影响因子：
4.6
通讯作者：
中科院分区：
文献类型：
--
作者：
心血管疾病（CVD）是一种多系统和多细胞的病理，通常与循环中高水平的致动脉粥样硬化脂蛋白有关。这些脂蛋白倾向于在不同组织（如血管壁和心脏）的细胞外基质中被保留和修饰，例如聚集的低密度脂蛋白（aggLDL）。在这些组织中，aggLDL的摄取产生胆固醇酯（CE）的显著增加。我们以前发现，CE的积累会改变心脏中的胰岛素反应。虽然胰岛素反应主要与葡萄糖的摄取和代谢有关，但其他研究表明，胰岛素将在该组织中发挥功能，例如调节钙循环和心肌收缩力。在这里，我们发现aggLDL诱导的脂质积累改变了HL-1心肌细胞中与心脏功能相关的基因表达谱，包括胰岛素反应和葡萄糖摄取（Insr，Ins 1，Pik 3 ip 1，Slc 2a 4基因表达），钙循环（Cacna 1 s和Gjc 2基因表达）和钙依赖性心肌收缩力（Myh 3）以及胆固醇流出（Abca 1）。使用高胆固醇血症ApoE-KO小鼠的体内模型概括了这些观察结果。总之，这些结果可以解释脂质蓄积在心肌中的有害作用，对脂质超载相关的CVD具有重要意义，包括胰岛素反应受损，脂质代谢紊乱，心脏结构改变和心血管事件易感性增加。
Cardiovascular disease (CVD) is a multisystemic and multicellular pathology that is generally associated with high levels of atherogenic lipoproteins in circulation. These lipoproteins tend to be retained and modified, for example, aggregated low-density lipoprotein (aggLDL), in the extracellular matrix of different tissues, such as the vascular wall and heart. The uptake of aggLDL generates a significant increase in cholesteryl ester (CE) in these tissues. We previously found that the accumulation of CE generates alterations in the insulin response in the heart. Although the insulin response is mainly associated with the uptake and metabolism of glucose, other studies have shown that insulin would fulfill functions in this tissue, such as regulating the calcium cycle and cardiac contractility. Here, we found that aggLDL induced-lipid accumulation altered the gene expression profile involved in processes essential for cardiac functionality, including insulin response and glucose uptake (Insr, Ins1, Pik3ip1, Slc2a4 gene expression), calcium cycle (Cacna1s and Gjc2 gene expression) and calcium-dependent cardiac contractility (Myh3), and cholesterol efflux (Abca1), in HL-1 cardiomyocytes. These observations were recapitulated using an in vivo model of hypercholesterolemic ApoE-KO mice. Altogether, these results may explain the deleterious effect of lipid accumulation in the myocardium, with important implications for lipid-overloaded associated CVD, including impaired insulin response, disrupted lipid metabolism, altered cardiac structure, and increased susceptibility to cardiovascular events.
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影响因子：
8.7
作者：
Llorente-Cortés, V;Martínez-González, J;Badimon, L
通讯作者：
Badimon, L
影响因子：
14.9
作者：
Martens M;Ammar A;Riutta A;Waagmeester A;Slenter DN;Hanspers K;A Miller R;Digles D;Lopes EN;Ehrhart F;Dupuis LJ;Winckers LA;Coort SL;Willighagen EL;Evelo CT;Pico AR;Kutmon M
通讯作者：
Kutmon M
影响因子：
3.7
作者：
Barriga M;Cal R;Cabello N;Llach A;Vallmitjana A;Benítez R;Badimon L;Cinca J;Llorente-Cortés V;Hove-Madsen L
通讯作者：
Hove-Madsen L
影响因子：
--
作者：
Lu M;Gursky O
通讯作者：
Gursky O
DOI：
10.1161/atvbaha.114.303887
发表时间：
2014-08-01
影响因子：
8.7
作者：
Bekkering, Siroon;Quintin, Jessica;Riksen, Niels P.
通讯作者：
Riksen, Niels P.