Zhao Lan, Oliver Eduardo, Maratou Klio, Atanur Santosh S, Dubois Olivier D, Cotroneo Emanuele, Chen Chien-Nien, Wang Lei, Arce Cristina, Chabosseau Pauline L, Ponsa-Cobas Joan, Frid Maria G, Moyon Benjamin, Webster Zoe, Aldashev Almaz, Ferrer Jorge, Rutter Guy A, Stenmark Kurt R, Aitman Timothy J, Wilkins Martin R
Centre for Pharmacology and Therapeutics, Division of Experimental Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, UK.
Physiological Genomics and Medicine Group, Medical Research Council Clinical Sciences Centre, Hammersmith Hospital, London W12 0NN, UK.
Nature. 2015 Aug 20;524(7565):356-60. doi: 10.1038/nature14620. Epub 2015 Aug 10.
The typical response of the adult mammalian pulmonary circulation to a low oxygen environment is vasoconstriction and structural remodelling of pulmonary arterioles, leading to chronic elevation of pulmonary artery pressure (pulmonary hypertension) and right ventricular hypertrophy. Some mammals, however, exhibit genetic resistance to hypoxia-induced pulmonary hypertension. We used a congenic breeding program and comparative genomics to exploit this variation in the rat and identified the gene Slc39a12 as a major regulator of hypoxia-induced pulmonary vascular remodelling. Slc39a12 encodes the zinc transporter ZIP12. Here we report that ZIP12 expression is increased in many cell types, including endothelial, smooth muscle and interstitial cells, in the remodelled pulmonary arterioles of rats, cows and humans susceptible to hypoxia-induced pulmonary hypertension. We show that ZIP12 expression in pulmonary vascular smooth muscle cells is hypoxia dependent and that targeted inhibition of ZIP12 inhibits the rise in intracellular labile zinc in hypoxia-exposed pulmonary vascular smooth muscle cells and their proliferation in culture. We demonstrate that genetic disruption of ZIP12 expression attenuates the development of pulmonary hypertension in rats housed in a hypoxic atmosphere. This new and unexpected insight into the fundamental role of a zinc transporter in mammalian pulmonary vascular homeostasis suggests a new drug target for the pharmacological management of pulmonary hypertension.
成年哺乳动物肺循环对低氧环境的典型反应是肺小动脉血管收缩和结构重塑，导致肺动脉压力（肺动脉高压）慢性升高以及右心室肥厚。然而，一些哺乳动物对低氧诱导的肺动脉高压表现出遗传抗性。我们利用近交系培育计划和比较基因组学来研究大鼠的这种差异，并确定基因Slc39a12是低氧诱导的肺血管重塑的主要调节因子。Slc39a12编码锌转运蛋白ZIP12。在此我们报告，在易患低氧诱导的肺动脉高压的大鼠、牛和人的重塑肺小动脉中，包括内皮细胞、平滑肌细胞和间质细胞在内的许多细胞类型中ZIP12的表达均增加。我们表明，肺血管平滑肌细胞中ZIP12的表达是低氧依赖性的，并且靶向抑制ZIP12可抑制暴露于低氧的肺血管平滑肌细胞中细胞内不稳定锌的升高及其在培养中的增殖。我们证明，ZIP12表达的基因破坏可减轻低氧环境中饲养的大鼠肺动脉高压的发展。这种对锌转运蛋白在哺乳动物肺血管稳态中的基本作用的新的意外见解提示了肺动脉高压药物治疗的新靶点。
