Cardiac expression of HMOX1 and PGF in sickle cell mice and haem-treated wild type mice dominates organ expression profiles via Nrf2 (Nfe2l2).
Cardiac expression of HMOX1 and PGF in sickle cell mice and haem-treated wild type mice dominates organ expression profiles via Nrf2 (Nfe2l2).
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DOI：
10.1111/bjh.16129
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发表时间：
2019-12
影响因子：
6.5
通讯作者：
Kato GJ
中科院分区：
文献类型：
--
作者：
Gbotosho OT;Ghosh S;Kapetanaki MG;Lin Y;Weidert F;Bullock GC;Ofori-Acquah SF;Kato GJ
溶血是镰状细胞病 (SCD) 的一个主要特征，会导致器官损伤。众所周知，血红素是一种溶血产物，可诱导降解它的酶血红素加氧酶-1 (HMOX1) 的表达。我们还表明，血红素诱导胎盘生长因子（PGF）的表达，但这些反应的器官特异性尚未明确。正如预期的那样，我们在转基因镰状细胞小鼠的网状内皮系统器官中发现了 Hmox1 和 Pgf 转录本的高水平表达，但在心脏中的表达却令人惊讶（P < 0.0001）。通过静脉注射外源血红素，这种模式在野生型小鼠中得到了很大程度的复制。在心脏中，血红素诱导 Hmox1（18 倍）、Pgf（4 倍）和血红素转运蛋白 Slc48a1（也称为 Hrg1；2.4 倍）的 mRNA 反应出乎意料地强烈。这与肝脏（已知的主要血红素解毒器官）相当。 NFE2L2（也称为 NRF2）转录因子在所有器官中介导 Hmox1 和 Hrg1 的大部分血红素诱导，但对 Pgf 的介导作用较小。我们的结果表明，心脏以令人惊讶的高基础水平表达血红素反应途径基因，并且与肝脏对循环血红素具有相似的转录反应。应进一步研究心脏在血红素反应中的作用。
Haemolysis is a major feature of sickle cell disease (SCD) that contributes to organ damage. It is well established that haem, a product of haemolysis, induces expression of the enzyme that degrades it, haem oxygenase-1 (HMOX1). We have also shown that haem induces expression of placental growth factor (PGF), but the organ specificity of these responses has not been well-defined. As expected, we found high level expression of Hmox1 and Pgf transcripts in the reticuloendothelial system organs of transgenic sickle cell mice, but surprisingly strong expression in the heart (P < 0.0001). This pattern was largely replicated in wild type mice by intravenous injection of exogenous haem. In the heart, haem induced unexpectedly strong mRNA responses for Hmox1 (18-fold), Pgf (4-fold), and the haem transporter Slc48a1 (also termed Hrg1; 2.4-fold). This was comparable to the liver, the principal known haem-detoxifying organ. The NFE2L2 (also termed NRF2) transcription factor mediated much of the haem induction of Hmox1 and Hrg1 in all organs, but less so for Pgf. Our results indicate that the heart expresses haem response pathway genes at surprisingly high basal levels and shares with the liver a similar transcriptional response to circulating haem. The role of the heart in haem response should be investigated further.
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