Open AccessIncreased Heme Levels in the Heart Lead to Exacerbated Ischemic Injury
Author(s) -
Sawicki Konrad Teodor,
Shang Meng,
Wu Rongxue,
Chang HsiangChun,
Khechaduri Arineh,
Sato Tatsuya,
Kamide Christine,
Liu Ting,
Naga Prasad Sathyamangla V.,
Ardehali Hossein
Publication year - 2015
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.115.002272
Subject(s) - heme , oxidative stress , heme oxygenase , medicine , hmox1 , heart failure , cardiac function curve , endocrinology , oxidative phosphorylation , programmed cell death , biochemistry , biology , apoptosis , enzyme
Background Heme is an essential iron‐containing molecule for cardiovascular physiology, but in excess it may increase oxidative stress. Failing human hearts have increased heme levels, with upregulation of the rate‐limiting enzyme in heme synthesis, δ‐aminolevulinic acid synthase 2 ( ALAS 2), which is normally not expressed in cardiomyocytes. We hypothesized that increased heme accumulation (through cardiac overexpression of ALAS 2) leads to increased oxidative stress and cell death in the heart. Methods and Results We first showed that ALAS 2 and heme levels are increased in the hearts of mice subjected to coronary ligation. To determine the causative role of increased heme in the development of heart failure, we generated transgenic mice with cardiac‐specific overexpression of ALAS 2. While ALAS 2 transgenic mice have normal cardiac function at baseline, their hearts display increased heme content, higher oxidative stress, exacerbated cell death, and worsened cardiac function after coronary ligation compared to nontransgenic littermates. We confirmed in cultured cardiomyoblasts that the increased oxidative stress and cell death observed with ALAS 2 overexpression is mediated by increased heme accumulation. Furthermore, knockdown of ALAS 2 in cultured cardiomyoblasts exposed to hypoxia reversed the increases in heme content and cell death. Administration of the mitochondrial antioxidant MitoTempo to ALAS 2‐overexpressing cardiomyoblasts normalized the elevated oxidative stress and cell death levels to baseline, indicating that the effects of increased ALAS 2 and heme are through elevated mitochondrial oxidative stress. The clinical relevance of these findings was supported by the finding of increased ALAS 2 induction and heme accumulation in failing human hearts from patients with ischemic cardiomyopathy compared to nonischemic cardiomyopathy. Conclusions Heme accumulation is detrimental to cardiac function under ischemic conditions, and reducing heme in the heart may be a novel approach for protection against the development of heart failure.