Patel Dhara, Alhawaj Raed, Wolin Michael S
Department of Physiology and Pulmonary Hypertension Center, New York Medical College, Valhalla, New York.
Department of Physiology and Pulmonary Hypertension Center, New York Medical College, Valhalla, New York
Am J Physiol Regul Integr Comp Physiol. 2014 Aug 15;307(4):R426-33. doi: 10.1152/ajpregu.00257.2013. Epub 2014 Jun 11.
Exposing mice to a chronic hypoxic treatment (10% oxygen, 21 days) that promotes pulmonary hypertension was observed to attenuate the pulmonary vasoconstriction response to acute hypoxia (HPV) both in vivo and in isolated pulmonary arteries. Since catalase restored the HPV response in isolated arteries, it appeared to be attenuated by extracellular hydrogen peroxide. Chronic hypoxia promoted the detection of elevated lung superoxide, extracellular peroxide, extracellular SOD expression, and protein kinase G (PKG) activation [based on PKG dimerization and vasodilator-stimulated phosphoprotein (VASP) phosphorylation], suggesting increased generation of extracellular peroxide and PKG activation may contribute to the suppression of HPV. Aorta from mice exposed to 21 days of hypoxia also showed evidence for extracellular hydrogen peroxide, suppressing the relaxation response to acute hypoxia. Peroxide appeared to partially suppress contractions to phenylephrine used in the study of in vitro hypoxic responses. Treatment of mice with the heme precursor δ-aminolevulinic acid (ALA; 50 mg·kg(-1)·day(-1)) during exposure to chronic hypoxia was examined as a pulmonary hypertension therapy because it could potentially activate beneficial cGMP-mediated effects through promoting a prolonged protoporphyrin IX (PpIX)-elicited activation of soluble guanylate cyclase. ALA attenuated pulmonary hypertension, increases in both superoxide and peroxide, and the suppression of in vitro and in vivo HPV responses. ALA generated prolonged detectible increases in PpIX and PKG-associated phosphorylation of VASP, suggesting PKG activation may contribute to suppression of pulmonary hypertension and prevention of alterations in extracellular peroxide that appear to be attenuating HPV responses caused by chronic hypoxia.
将小鼠暴露于促进肺动脉高压的慢性低氧治疗（10%氧气，21天）后，观察到在体内和离体肺动脉中，其对急性低氧（低氧性肺血管收缩，HPV）的肺血管收缩反应均减弱。由于过氧化氢酶可恢复离体动脉中的HPV反应，因此似乎是细胞外过氧化氢导致了该反应减弱。慢性低氧促进了肺中超氧化物、细胞外过氧化物、细胞外超氧化物歧化酶（SOD）表达以及蛋白激酶G（PKG）激活的检测[基于PKG二聚化和血管舒张刺激磷蛋白（VASP）磷酸化]，这表明细胞外过氧化物生成增加和PKG激活可能导致HPV受到抑制。暴露于低氧21天的小鼠的主动脉也显示出存在细胞外过氧化氢的证据，其抑制了对急性低氧的舒张反应。在体外低氧反应研究中，过氧化物似乎部分抑制了对去氧肾上腺素的收缩反应。在慢性低氧暴露期间，用血红素前体δ-氨基乙酰丙酸（ALA；50 mg·kg⁻¹·天⁻¹）治疗小鼠作为一种肺动脉高压治疗方法进行了研究，因为它可能通过促进原卟啉IX（PpIX）引发的可溶性鸟苷酸环化酶的长期激活来激活有益的环磷酸鸟苷（cGMP）介导的效应。ALA减轻了肺动脉高压、超氧化物和过氧化物的增加以及体外和体内HPV反应的抑制。ALA使PpIX以及VASP的PKG相关磷酸化产生了可检测到的长期增加，这表明PKG激活可能有助于抑制肺动脉高压以及预防细胞外过氧化物的改变，而这些改变似乎正在减弱由慢性低氧引起的HPV反应。
