Inhibition of P110α and P110δ catalytic subunits of PI3 kinase reverses impaired arterial healing after injury in hypercholesterolemic male mice.
Inhibition of P110α and P110δ catalytic subunits of PI3 kinase reverses impaired arterial healing after injury in hypercholesterolemic male mice.
复制标题
抑制 PI3 激酶的 P110α 和 P110α 催化亚基可逆转高胆固醇血症雄性小鼠受伤后受损的动脉愈合。
DOI：
10.1152/ajpcell.00600.2020
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Rosenbaum,MichaelA
中科院分区：
文献类型：
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作者：
Chaudhuri,Pinaki;Smith,AndrewH;Graham,LindaM;Rosenbaum,MichaelA
内皮细胞（EC）迁移对于愈合动脉损伤（如血管成形术中发生的损伤）至关重要。动脉损伤后受损的再内皮化导致血管血栓形成、内膜增生和再狭窄。氧化脂质产物，包括溶血磷脂酰胆碱（lysoPC），诱导典型瞬时受体电位6（TRPC 6）外化，导致[Ca 2 +]i增加、钙蛋白酶激活以及抑制迁移的EC细胞骨架结构改变。磷脂酰肌醇3-激酶（PI 3 K）的p110α和p110δ催化亚基异构体在体外调节lysoPC诱导的TRPC 6外化。本研究的目的是评估这些体外结果与高胆固醇血症小鼠剥脱性损伤后动脉愈合的体内相关性，高胆固醇血症小鼠接受PI 3 K的p110α和p110δ亚型的药理学抑制剂和一般PI 3 K抑制剂治疗。药理学抑制PI 3 K的p110α或p110δ亚型可部分保护高胆固醇血症雄性小鼠的愈合，与一般PI 3 K抑制剂相似。有趣的是，p110α、p110δ和一般的PI 3 K抑制剂不能改善高胆固醇血症雌性小鼠损伤后的动脉愈合。这些结果表明亚型特异性PI 3 K抑制剂在动脉损伤/干预后男性患者中的潜在新作用。结果还确定了心血管系统中PI 3 K抑制反应的显著性别差异，女性通常具有心脏保护作用。这项研究为研究PI 3 K抑制反应的性别差异机制提供了基础，以开发更普遍适用的治疗方案。
Endothelial cell (EC) migration is critical for healing arterial injuries, such as those that occur with angioplasty. Impaired re-endothelialization following arterial injury contributes to vessel thrombogenicity, intimal hyperplasia, and restenosis. Oxidized lipid products, including lysophosphatidylcholine (lysoPC), induce canonical transient receptor potential 6 (TRPC6) externalization leading to increased [Ca2+]i, activation of calpains, and alterations of the EC cytoskeletal structure that inhibit migration. The p110α and p110δ catalytic subunit isoforms of phosphatidylinositol 3-kinase (PI3K) regulate lysoPC-induced TRPC6 externalization in vitro. The goal of this study was to assess the in vivo relevance of those in vitro findings to arterial healing following a denuding injury in hypercholesterolemic mice treated with pharmacologic inhibitors of the p110α and p110δ isoforms of PI3K and a general PI3K inhibitor. Pharmacologic inhibition of the p110α or the p110δ isoform of PI3K partially preserves healing in hypercholesterolemic male mice, similar to a general PI3K inhibitor. Interestingly, the p110α, p110δ, and the general PI3K inhibitor do not improve arterial healing after injury in hypercholesterolemic female mice. These results indicate a potential new role for isoform-specific PI3K inhibitors in male patients following arterial injury/intervention. The results also identify significant sex differences in the response to PI3K inhibition in the cardiovascular system, where female sex generally has a cardioprotective effect. This study provides a foundation to investigate the mechanism for the sex differences in response to PI3K inhibition to develop a more generally applicable treatment option.