Oknińska Marta, Paterek Aleksandra, Grzanka Małgorzata, Zajda Karolina, Surzykiewicz Mateusz, Rolski Filip, Zambrowska Zuzanna, Torbicki Adam, Kurzyna Marcin, Kieda Claudine, Piekiełko-Witkowska Agnieszka, Mączewski Michał
Department of Clinical Physiology, Centre of Translational Research, Centre of Postgraduate Medical Education, Warsaw, Poland.
Department of Biochemistry and Molecular Biology, Centre of Translational Research, Centre of Postgraduate Medical Education, Warsaw, Poland.
Br J Pharmacol. 2024 Oct;181(20):4050-4066. doi: 10.1111/bph.16482. Epub 2024 Jul 1.
Pulmonary hypertension (PH) results from pulmonary vasculopathy, initially leading to a compensatory right ventricular (RV) hypertrophy, and eventually to RV failure. Hypoxia can trigger both pulmonary vasculopathy and RV failure. Therefore, we tested if myo-inositol trispyrophosphate (ITPP), which facilitates oxygen dissociation from haemoglobin, can relieve pulmonary vasculopathy and RV hypoxia, and eventually prevent RV failure and mortality in the rat model of monocrotaline-induced PH.
Rats were injected with monocrotaline (PH) or saline (control) and received ITPP or placebo for 5 weeks. Serial echocardiograms were obtained to monitor the disease, pressure-volume loops were recorded and evaluated, myocardial pO was measured using a fluorescent probe, and histological and molecular analyses were conducted at the conclusion of the experiment.
ITPP reduced PH-related mortality. It had no effect on progressive increase in pulmonary vascular resistance, yet significantly relieved intramyocardial RV hypoxia, which was associated with improvement of RV function and reduction of RV wall stress. ITPP also tended to prevent increased hypoxia inducible factor-1α expression in RV cardiac myocytes but did not affect RV capillary density.
Our study suggests that strategies aimed at increasing oxygen delivery to hypoxic RV in PH could potentially be used as adjuncts to other therapies that target pulmonary vessels, thus increasing the ability of the RV to withstand increased afterload and reducing mortality. ITPP may be one such potential therapy.
肺动脉高压（PH）由肺血管病变引起，最初导致代偿性右心室（RV）肥厚，最终导致RV衰竭。缺氧可引发肺血管病变和RV衰竭。因此，我们测试了促进血红蛋白氧解离的肌醇三磷酸（ITPP）是否能缓解肺血管病变和RV缺氧，并最终预防单氰胺诱导的PH大鼠模型中的RV衰竭和死亡。
给大鼠注射单氰胺（PH组）或生理盐水（对照组），并给予ITPP或安慰剂，持续5周。获取系列超声心动图以监测病情，记录并评估压力-容积环，使用荧光探针测量心肌pO，实验结束时进行组织学和分子分析。
ITPP降低了与PH相关的死亡率。它对肺血管阻力的逐渐增加没有影响，但显著缓解了心肌内RV缺氧，这与RV功能改善和RV壁应力降低有关。ITPP还倾向于防止RV心肌细胞中缺氧诱导因子-1α表达增加，但不影响RV毛细血管密度。
我们的研究表明，旨在增加PH中缺氧RV氧输送的策略可能潜在地用作针对肺血管的其他疗法的辅助手段，从而提高RV承受增加的后负荷的能力并降低死亡率。ITPP可能是一种这样的潜在疗法。
