The Metabolic Theory of Pulmonary Arterial Hypertension
The Metabolic Theory of Pulmonary Arterial Hypertension
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DOI：
10.1161/circresaha.115.301130
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发表时间：
2014-06-20
影响因子：
20.1
通讯作者：
Michelakis, Evangelos D.
中科院分区：
文献类型：
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作者：
Paulin, Roxane;Michelakis, Evangelos D.
肺动脉高压（PAH）中已经描述了许多分子异常，这使得候选治疗方法对患者的翻译复杂化，因为通常情况下，一种治疗方法只针对一种异常。认识到除肺动脉血管细胞外，其他组织和细胞（如免疫细胞、右心室心肌细胞、骨骼肌）也参与PAH综合征，进一步使最佳治疗靶点的确定复杂化。在这里，我们描述了一种代谢理论，该理论提出多环芳烃中许多明显不相关的分子异常确实有一个共同点；它们引起或促进肺血管细胞的线粒体抑制（抑制葡萄糖氧化）；反过来，这种线粒体抑制的下游信号也可以解释许多以前没有联系的分子事件。线粒体上下游信号的整合与癌症有相似之处，可以解释PAH血管表型的许多特征，包括增殖和细胞凋亡抵抗。这种葡萄糖氧化的抑制（伴随糖酵解的继发性上调）也是肺外组织异常的基础，表明存在全局代谢紊乱。代谢理论将线粒体置于了解多环芳烃发病机制和开发新型诊断和治疗工具的中心位置。目前的多环芳烃治疗方法都是针对1种异常（例如，内皮素-1的上调），并不是专门针对多环芳烃，而是针对系统性血管疾病。与现有的治疗方法相比，线粒体靶向治疗具有同时处理多个分子异常的优势（因此可能更有效），并且由于它们处理pah特异性生物学，因此具有更高的特异性。
Numerous molecular abnormalities have been described in pulmonary arterial hypertension (PAH), complicating the translation of candidate therapies to patients because, typically, 1 treatment addresses only 1 abnormality. The realization that in addition to pulmonary artery vascular cells, other tissues and cells are involved in the syndrome of PAH (eg, immune cells, right ventricular cardiomyocytes, skeletal muscle) further complicates the identification of optimal therapeutic targets. Here, we describe a metabolic theory that proposes that many apparently unrelated molecular abnormalities in PAH do have a common denominator; they either cause or promote a mitochondrial suppression (inhibition of glucose oxidation) in pulmonary vascular cells; in turn, the signaling downstream from this mitochondrial suppression can also explain numerous molecular events previously not connected. This integration of signals upstream and downstream of mitochondria has similarities to cancer and can explain many features of the PAH vascular phenotype, including proliferation and apoptosis resistance. This suppression of glucose oxidation (with secondary upregulation of glycolysis) also underlies the abnormalities in extrapulmonary tissues, suggesting a global metabolic disturbance. The metabolic theory places mitochondria at the center stage for our understanding of PAH pathogenesis and for the development of novel diagnostic and therapeutic tools. Current PAH therapies are each addressing 1 abnormality (eg, upregulation of endothelin-1) and were not developed specifically for PAH but for systemic vascular diseases. Compared with the available therapies, mitochondria-targeting therapies have the advantage of addressing multiple molecular abnormalities simultaneously (thus being potentially more effective) and achieving higher specificity because they address PAH-specific biology.