Genetic Analysis Reveals a Longevity-Associated Protein Modulating Endothelial Function and Angiogenesis.
Genetic Analysis Reveals a Longevity-Associated Protein Modulating Endothelial Function and Angiogenesis.
复制标题
DOI：
10.1161/circresaha.117.305875
复制
发表时间：
2015-07-31
影响因子：
20.1
通讯作者：
Puca AA
中科院分区：
文献类型：
--
作者：
Villa F;Carrizzo A;Spinelli CC;Ferrario A;Malovini A;Maciąg A;Damato A;Auricchio A;Spinetti G;Sangalli E;Dang Z;Madonna M;Ambrosio M;Sitia L;Bigini P;Calì G;Schreiber S;Perls T;Fucile S;Mulas F;Nebel A;Bellazzi R;Madeddu P;Vecchione C;Puca AA
长寿个体表现为衰老延缓，其特征是心血管内稳态进行性丧失，伴随着内皮型一氧化氮合酶活性降低，内皮功能障碍，以及缺血损伤后组织修复的损害。利用长寿个体的遗传分析，揭示生理性衰老的主要分子调控因素和心血管疾病治疗的新靶点。结果表明，在3个独立的群体中，含有杀菌/通透性增加折叠的家族B成员4(BPIFB4)的rs2070325(Ile229Val)的多态变异在3个独立的群体中以隐性遗传模式表现出显著的长寿。此外，BPIFB4的表达有助于通过调节蛋白质合成来维持细胞和血管的动态平衡。BPIFB4被蛋白-激酶-R样内质网蛋白激酶磷酸化/激活，诱导其与14-3-3和热休克蛋白90的络合，而长寿相关突变体促进了BPIFB4的结合。在分离的血管中，BPIFB4被机械应力上调，它的下调抑制了内皮依赖的血管松弛。在高血压大鼠和老年小鼠中，长寿相关变异体BPIFB4的基因转移可以恢复内皮型一氧化氮合酶信号，拯救内皮功能障碍，降低血压水平。此外，BPIFB4与血管修复有关。BPIFB4在长寿个体的循环CD34+细胞中大量表达，其在内皮祖细胞中的表达下调使其无法向趋化因子SDF-1迁移。在外周缺血的小鼠模型中，长寿相关突变体BPIFB4的系统基因治疗促进了造血干细胞的募集、修复性血管形成和缺血肌肉的再灌注。长寿相关突变体-BPIFB4可能是对抗内皮功能障碍和促进血管修复过程的一种新的治疗工具。
Long living individuals show delay of aging, which is characterized by the progressive loss of cardiovascular homeostasis, along with reduced endothelial nitric oxide synthase activity, endothelial dysfunction, and impairment of tissue repair after ischemic injury. Exploit genetic analysis of long living individuals to reveal master molecular regulators of physiological aging and new targets for treatment of cardiovascular disease. We show that the polymorphic variant rs2070325 (Ile229Val) in bactericidal/permeability-increasing fold-containing-family-B-member-4 (BPIFB4) associates with exceptional longevity, under a recessive genetic model, in 3 independent populations. Moreover, the expression of BPIFB4 is instrumental to maintenance of cellular and vascular homeostasis through regulation of protein synthesis. BPIFB4 phosphorylation/activation by protein-kinase-R–like endoplasmic reticulum kinase induces its complexing with 14-3-3 and heat shock protein 90, which is facilitated by the longevity-associated variant. In isolated vessels, BPIFB4 is upregulated by mechanical stress, and its knock-down inhibits endothelium-dependent vasorelaxation. In hypertensive rats and old mice, gene transfer of longevity-associated variant-BPIFB4 restores endothelial nitric oxide synthase signaling, rescues endothelial dysfunction, and reduces blood pressure levels. Furthermore, BPIFB4 is implicated in vascular repair. BPIFB4 is abundantly expressed in circulating CD34+ cells of long living individuals, and its knock-down in endothelial progenitor cells precludes their capacity to migrate toward the chemoattractant SDF-1. In a murine model of peripheral ischemia, systemic gene therapy with longevity-associated variant-BPIFB4 promotes the recruitment of hematopoietic stem cells, reparative vascularization, and reperfusion of the ischemic muscle. Longevity-associated variant-BPIFB4 may represent a novel therapeutic tool to fight endothelial dysfunction and promote vascular reparative processes.