Preservation of myocardial contractility during acute hypoxia with OMX-CV, a novel oxygen delivery biotherapeutic.
Preservation of myocardial contractility during acute hypoxia with OMX-CV, a novel oxygen delivery biotherapeutic.
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DOI：
10.1371/journal.pbio.2005924
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发表时间：
2018-10
期刊：
影响因子：
9.8
通讯作者：
Maltepe E
中科院分区：
文献类型：
--
作者：
Boehme J;Le Moan N;Kameny RJ;Loucks A;Johengen MJ;Lesneski AL;Gong W;Goudy BD;Davis T;Tanaka K;Davis A;He Y;Long-Boyle J;Ivaturi V;Gobburu JVS;Winger JA;Cary SP;Datar SA;Fineman JR;Krtolica A;Maltepe E
心脏表现出身体中任何器官的每组织质量的最高基础氧（O2）消耗，并且独特地依赖于有氧代谢来维持收缩功能。在急性缺氧状态下，身体的反应是心输出量代偿性增加，进一步增加心肌O2需求，使心脏易受缺血性应激和心肌功能障碍的影响。在这里，我们测试了一种新的工程蛋白质的效用，该蛋白质来源于基于血红素的一氧化氮（NO）/氧（H-NOX）家族的细菌蛋白质作为缺氧心肌的O2递送生物素（Omniox-cardiovascular [OMX-CV]）。由于其独特的结合特性，基于H-NOX的变体有效地将O2递送到缺氧组织，但不是那些处于生理O2张力的组织。此外，基于H-NOX的变体表现出对O2具有特异性的可调结合，对NO具有亚生理反应性，避免了基于血红蛋白（Hb）的O2载体（HBOC）表现出的显著毒性。幼年羔羊镇静，机械通气，并仪器测量心血管参数。插入双心室导纳导管进行压力-容积（PV）分析。采用10%O2通气诱导全身性缺氧。缺氧15分钟后，用OMX-CV（200 mg/kg IV）或溶剂处理羔羊。急性缺氧引起心率（HR）、肺血流量（PBF）和肺血管阻力（PVR）显著增加（p < 0.05）。在1小时时，溶剂处理的羔羊表现出严重缺氧和双心室收缩功能显著降低。然而，在OMX-CV治疗的动物中，心肌氧合得到改善，而不会对全身或PVR产生负面影响，并且右心室（RV）和左心室（LV）收缩功能均维持在缺氧前基线水平。这些数据表明，OMX-CV是一种有前途的和安全的氧气输送生物制剂，用于在急性缺氧的情况下保护心肌收缩力。虽然血红蛋白是用于维持后生动物中组织氧合的主要氧递送分子，但许多生物体具有其他含血红素的蛋白质，其可以结合氧和其他双原子气体。在这里，我们测试了在热稳定细菌Thermoanaerobic tengcongensis中发现的含血红素蛋白质的H-NOX家族的成员是否可以被工程化以将氧气输送到大型哺乳动物的严重缺氧组织中。这类分子具有高氧亲和力和最小的一氧化氮反应性的优点。我们证明，这些分子可以有效地提供氧气的羔羊心脏诱导严重缺氧，而不会过度暴露的动物氧气或触发全身血管反应。因此，这些分子代表了一类新型的氧递送生物治疗剂，以特异性靶向缺氧组织床，而没有基于血红蛋白的氧载体的毒性问题。由于组织缺氧是许多疾病过程的中心特征，因此这种治疗方法可能具有广泛的临床适用性。
The heart exhibits the highest basal oxygen (O2) consumption per tissue mass of any organ in the body and is uniquely dependent on aerobic metabolism to sustain contractile function. During acute hypoxic states, the body responds with a compensatory increase in cardiac output that further increases myocardial O2 demand, predisposing the heart to ischemic stress and myocardial dysfunction. Here, we test the utility of a novel engineered protein derived from the heme-based nitric oxide (NO)/oxygen (H-NOX) family of bacterial proteins as an O2 delivery biotherapeutic (Omniox-cardiovascular [OMX-CV]) for the hypoxic myocardium. Because of their unique binding characteristics, H-NOX–based variants effectively deliver O2 to hypoxic tissues, but not those at physiologic O2 tension. Additionally, H-NOX–based variants exhibit tunable binding that is specific for O2 with subphysiologic reactivity towards NO, circumventing a significant toxicity exhibited by hemoglobin (Hb)-based O2 carriers (HBOCs). Juvenile lambs were sedated, mechanically ventilated, and instrumented to measure cardiovascular parameters. Biventricular admittance catheters were inserted to perform pressure-volume (PV) analyses. Systemic hypoxia was induced by ventilation with 10% O2. Following 15 minutes of hypoxia, the lambs were treated with OMX-CV (200 mg/kg IV) or vehicle. Acute hypoxia induced significant increases in heart rate (HR), pulmonary blood flow (PBF), and pulmonary vascular resistance (PVR) (p < 0.05). At 1 hour, vehicle-treated lambs exhibited severe hypoxia and a significant decrease in biventricular contractile function. However, in OMX-CV–treated animals, myocardial oxygenation was improved without negatively impacting systemic or PVR, and both right ventricle (RV) and left ventricle (LV) contractile function were maintained at pre-hypoxic baseline levels. These data suggest that OMX-CV is a promising and safe O2 delivery biotherapeutic for the preservation of myocardial contractility in the setting of acute hypoxia. While hemoglobin is the primary oxygen delivery molecule used to maintain tissue oxygenation in metazoans, many organisms have other heme-containing proteins that can bind oxygen and other diatomic gases. Here, we tested whether a member of the H-NOX family of heme-containing proteins found in the thermostable bacterium Thermoanaerobacter tengcongensis can be engineered to deliver oxygen to severely hypoxic tissues in large mammals. This class of molecules has the advantage of high oxygen affinity and minimal nitric oxide reactivity. We demonstrate that these molecules can effectively deliver oxygen to a lamb heart with induced severe hypoxia, without overexposing the animal to oxygen or triggering systemic vascular reactivity. These molecules thus represent a novel class of oxygen delivery biotherapeutics to specifically target hypoxic tissue beds without the toxicity concerns of hemoglobin-based oxygen carriers. As tissue hypoxia is a central feature of many disease processes, this therapeutic approach may have broad clinical applicability.
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影响因子：
1.5
作者：
Chan, WL;Tang, NLS;Tam, MSC
通讯作者：
Tam, MSC
影响因子：
4.1
作者：
Dunne, Jacqueline;Caron, Alexis;Cooper, Chris E.
通讯作者：
Cooper, Chris E.
影响因子：
5.2
作者：
Gould, SA;Moore, EE;Moss, GS
通讯作者：
Moss, GS
影响因子：
5.5
作者：
DONNELLY, DF;DOYLE, TP
通讯作者：
DOYLE, TP
DOI：
10.1186/s13054-015-0996-4
发表时间：
2015-08-17
期刊：
Critical care (London, England)
影响因子：
--
作者：
Helmerhorst HJ;Schultz MJ;van der Voort PH;de Jonge E;van Westerloo DJ
通讯作者：
van Westerloo DJ