Vasoprotective effect of PDGF-CC mediated by HMOX1 rescues retinal degeneration
Vasoprotective effect of PDGF-CC mediated by HMOX1 rescues retinal degeneration
复制标题
HMOX1 介导的 PDGF-CC 的血管保护作用可挽救视网膜变性
DOI：
10.1073/pnas.1404140111
复制
发表时间：
2014-10-14
影响因子：
11.1
通讯作者：
Liu, Xialin
中科院分区：
文献类型：
--
作者：
He, Chang;Zhao, Chen;Liu, Xialin
意义PDGF-CC在许多生物学过程中起关键作用，如发育、肿瘤生长和血管生成。然而，其在血管存活/消退中的作用和潜在机制仍然未知。在这里，使用不同的功能丧失和功能获得测定和多模型系统，我们表明PDGF-CC是维持血管存活所需的关键血管保护因子。从机制上讲，我们发现血红素氧合酶-1（HMOX 1）活性对PDGF-CC的血管保护/存活作用至关重要。鉴于血管变性在大多数退行性疾病中的普遍参与，PDGF-CC可能在治疗不同类型的退行性疾病中具有治疗用途。我们的研究结果指出，PDGF-CC水平应密切监测在各种病理条件下，以确保正常的血管存活。血管变性几乎涉及所有类型的退行性疾病。因此，非常需要增强血管保护和存活的策略。在这项研究中，使用不同的动物模型和培养的细胞，我们表明，PDGF-CC是一种有效的血管保护和生存因子。在各种动物模型中，通过基因缺失导致的PDGF-CC缺陷加剧了血管退化/变性。重要的是，用PDGF-CC蛋白治疗不仅增加了氧诱导的血管消退模型中视网膜血管的存活，而且还显著挽救了视网膜色素变性疾病模型中的视网膜和血管变性。从机制上讲，我们发现，血红素加氧酶-1（HMOX 1）的活性是至关重要的血管保护/PDGF-CC的生存效果，因为HMOX 1的封锁完全废除了PDGF-CC在体外和体内的保护作用。我们进一步发现，PDGF-CC的血管保护作用需要两种PDGF受体，PDGFR-β和PDGFR-α。因此，我们的数据表明，PDGF-CC在维持血管存活方面发挥着关键作用，并且可能在治疗各种类型的退行性疾病方面具有治疗价值。
Significance PDGF-CC plays critical roles in many biological processes, such as development, tumor growth, and angiogenesis. However, its role in blood vessel survival/regression and the underlying mechanisms remain unknown. Here, using different loss- and gain-of-function assays and multiple model systems, we show that PDGF-CC is a critical vascular protective factor required to maintain blood vessel survival. Mechanistically, we found that heme oxygenase-1 (HMOX1) activity is crucial for the vascular protective/survival effect of PDGF-CC. Given the general involvement of vascular degeneration in most degenerative diseases, PDGF-CC may be of therapeutic use in treating different types of degenerative disorders. Our findings point out that the PDGF-CC level should be monitored closely in various pathological conditions to ensure normal blood vessel survival. Blood vessel degeneration is critically involved in nearly all types of degenerative diseases. Therefore strategies to enhance blood vessel protection and survival are highly needed. In this study, using different animal models and cultured cells, we show that PDGF-CC is a potent vascular protective and survival factor. PDGF-CC deficiency by genetic deletion exacerbated blood vessel regression/degeneration in various animal models. Importantly, treatment with PDGF-CC protein not only increased the survival of retinal blood vessels in a model of oxygen-induced blood vessel regression but also markedly rescued retinal and blood vessel degeneration in a disease model of retinitis pigmentosa. Mechanistically, we revealed that heme oxygenase-1 (HMOX1) activity is critically required for the vascular protective/survival effect of PDGF-CC, because blockade of HMOX1 completely abolished the protective effect of PDGF-CC in vitro and in vivo. We further found that both PDGF receptors, PDGFR-β and PDGFR-α, are required for the vasoprotective effect of PDGF-CC. Thus our data show that PDGF-CC plays a pivotal role in maintaining blood vessel survival and may be of therapeutic value in treating various types of degenerative diseases.