Heme Levels Are Increased in Human Failing Hearts

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• 作者：Arineh Khechaduri ; MS ; Marina Bayeva ; PhD ; Hsiang-Chun Chang ; BA ; Hossein Ardehali ; MD ; PhD ; ^{h-ardehali@northwestern.edu}
• 关键词：ALAS2 ; heart failure ; heme ; iron ; mitochondria
• 刊名：Journal of the American College of Cardiology
• 出版年：2013
• 出版时间：7 May, 2013
• 年：2013
• 卷：61
• 期：18
• 页码：1884-1893
• 全文大小：1026 K

文摘

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Objectives

The goal of this study was to characterize the regulation of heme and non-heme iron in human failing hearts.

Background

Iron is an essential molecule for cellular physiology, but in excess it facilitates oxidative stress. Mitochondria are the key regulators of iron homeostasis through heme and iron-sulfur cluster synthesis. Because mitochondrial function is depressed in failing hearts and iron accumulation can lead to oxidative stress, we hypothesized that iron regulation may also be impaired in heart failure (HF).

Methods

We measured mitochondrial and cytosolic heme and non-heme iron levels in failing human hearts retrieved during cardiac transplantation surgery. In addition, we examined the expression of genes regulating cellular iron homeostasis, the heme biosynthetic pathway, and micro-RNAs that may potentially target iron regulatory networks.

Results

Although cytosolic non-heme iron levels were reduced in HF, mitochondrial iron content was maintained. Moreover, we observed a significant increase in heme levels in failing hearts, with corresponding feedback inhibition of the heme synthetic enzymes and no change in heme degradation. The rate-limiting enzyme in heme synthesis, delta-aminolevulinic acid synthase 2 (ALAS2), was significantly upregulated in HF. Overexpression of ALAS2 in H9c2 cardiac myoblasts resulted in increased heme levels, and hypoxia and erythropoietin treatment increased heme production through upregulation of ALAS2. Finally, increased heme levels in cardiac myoblasts were associated with excess production of reactive oxygen species and cell death, suggesting a maladaptive role for increased heme in HF.

Conclusions

Despite global mitochondrial dysfunction, heme levels are maintained above baseline in human failing hearts.