Heme-bound iron activates placenta growth factor in erythroid cells via erythroid Kruppel-like factor

被引：39

作者：

Wang, Xunde ^{[1
]}

Mendelsohn, Laurel ^{[1
]}

Rogers, Heather ^{[2
]}

Leitman, Susan ^{[3
]}

Raghavachari, Nalini ^{[4
]}

Yang, Yanqin ^{[1
]}

Yau, Yu Ying ^{[3
]}

Tallack, Michael ^{[5
]}

Perkins, Andrew ^{[5
]}

Taylor, James G. ^{[1
]}

Noguchi, Constance Tom ^{[2
]}

Kato, Gregory J. ^{[6
,7
]}

机构：

[1] NHLBI, NIH, Bethesda, MD 20892 USA

[2] NIDDK, NIH, Bethesda, MD 20892 USA

[3] NIH, Ctr Clin, Bethesda, MD 20892 USA

[4] NIA, NIH, Bethesda, MD 20892 USA

[5] Mater Hosp, Mater Med Res Inst, Brisbane, Qld, Australia

[6] Univ Pittsburgh, Div Hematol Oncol, Dept Med, Pittsburgh, PA 15261 USA

[7] Univ Pittsburgh, Heart Lung Blood & Vasc Med Inst, Pittsburgh, PA 15261 USA

来源：

BLOOD | 2014年 / 124卷 / 06期

基金：

美国国家卫生研究院;

关键词：

PULMONARY ARTERIAL-HYPERTENSION; RIGHT HEART CATHETERIZATION; PLASMA ENDOTHELIN-1 LEVELS; GLOBIN GENE-EXPRESSION; ACUTE CHEST SYNDROME; PRIMITIVE ERYTHROPOIESIS; RECEPTOR ANTAGONISTS; ANGIOGENIC FACTORS; DISEASE; TRANSCRIPTION;

D O I：

10.1182/blood-2013-11-539718

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

In adults with sickle cell disease (SCD), markers of iron burden are associated with excessive production of the angiogenic protein placenta growth factor (PlGF) and high estimated pulmonary artery pressure. Enforced PlGF expression in mice stimulates production of the potent vasoconstrictor endothelin-1, producing pulmonary hypertension. We now demonstrate heme-bound iron (hemin) induces PlGF mRNA >200-fold in a dose-and time-dependent fashion. In murine and human erythroid cells, expression of erythroid Kruppel-like factor (EKLF) precedes PlGF, and its enforced expression in human erythroid progenitor cells induces PlGF mRNA. Hemin-induced expression of PlGF is abolished in EKLF-deficient murine erythroid cells but rescued by conditional expression of EKLF. Chromatin immunoprecipitation reveals that EKLF binds to the PlGF promoter region. SCD patients show higher level expression of both EKLF and PlGF mRNA in circulating blood cells, and markers of iron overload are associated with high PlGF and early mortality. Finally, PlGF association with iron burden generalizes to other human diseases of iron overload. Our results demonstrate a specific mechanistic pathway induced by excess iron that is linked in humans with SCD and in mice to markers of vasculopathy and pulmonary hypertension. These trials were registered at www.clinicaltrials.gov as #NCT00007150, #NCT00023296, #NCT00081523, and #NCT00352430.

引用

页码：946 / 954

页数：9

共 67 条

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