IRCCS Neuromed, 86077, Pozzilli (IS), Italy.
Department of Medicine and Surgery, University of Salerno, Fisciano, 84084, (SA), Italy.
Sci Rep. 2017 Aug 29;7(1):9706. doi: 10.1038/s41598-017-10341-x.
BPIFB4 is associated with exceptional longevity: four single-nucleotide polymorphisms distinguish the wild-type form from a longevity-associated variant conferring positive effects on blood pressure. The effect of a rare variant (RV; allele frequency, 4%) on blood pressure is unknown. Here, we show that overexpression of RV-BPIFB4 in ex-vivo mouse vessels impairs phosphorylation of endothelial nitric oxide synthase (eNOS), blunting acetylcholine-evoked vasorelaxation; in vivo, virally mediated overexpression of RV-BPIFB4 increases blood pressure, an action absent in eNOS-deficient mice. In humans, we found RV carriers to have increased diastolic blood pressure, a finding that was more marked in subjects on anti-hypertensive medication; moreover, recombinant RV-BPIFB4 protein impaired eNOS function in ex-vivo human vessels. Thus, RV-BPIFB4 acts directly on blood pressure homeostasis and may represent a novel biomarker of vascular dysfunction and hypertension.
BPIFB4 与超长寿命有关：四个单核苷酸多态性将野生型与一种与寿命相关的变体区分开来，后者对血压有积极影响。罕见变异（RV；等位基因频率为 4%）对血压的影响尚不清楚。在这里，我们表明 RV-BPIFB4 在体外培养的小鼠血管中的过表达会损害内皮型一氧化氮合酶（eNOS）的磷酸化，从而削弱乙酰胆碱引起的血管舒张；在体内，病毒介导的 RV-BPIFB4 的过表达会增加血压，而在 eNOS 缺陷小鼠中则没有这种作用。在人类中，我们发现 RV 携带者的舒张压升高，这一发现在服用抗高血压药物的患者中更为明显；此外，重组 RV-BPIFB4 蛋白在体外培养的人类血管中损害了 eNOS 的功能。因此，RV-BPIFB4 直接作用于血压稳态，可能代表血管功能障碍和高血压的新型生物标志物。
