title: Increased Heme Levels in the Heart Lead to Exacerbated Ischemic Injury.
abstract: 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 (ALAS2), which is normally not expressed in cardiomyocytes. We hypothesized that increased heme accumulation (through cardiac overexpression of ALAS2) leads to increased oxidative stress and cell death in the heart.
  
  
  RESULTS
  We first showed that ALAS2 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 ALAS2. While ALAS2 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 ALAS2 overexpression is mediated by increased heme accumulation. Furthermore, knockdown of ALAS2 in cultured cardiomyoblasts exposed to hypoxia reversed the increases in heme content and cell death. Administration of the mitochondrial antioxidant MitoTempo to ALAS2-overexpressing cardiomyoblasts normalized the elevated oxidative stress and cell death levels to baseline, indicating that the effects of increased ALAS2 and heme are through elevated mitochondrial oxidative stress. The clinical relevance of these findings was supported by the finding of increased ALAS2 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.
authors.affiliation: Feinberg Cardiovascular Research Institute (FCVRI), Northwestern University, Chicago, IL (K.T.S., M.S., R.W., H.C.C., A.K., T.S., C.K., T.L., H.A.).
authors.forename: Konrad Teodor
authors.initials: KT
authors.lastname: Sawicki
authors.affiliation: Feinberg Cardiovascular Research Institute (FCVRI), Northwestern University, Chicago, IL (K.T.S., M.S., R.W., H.C.C., A.K., T.S., C.K., T.L., H.A.).
authors.forename: Meng
authors.initials: M
authors.lastname: Shang
authors.affiliation: Feinberg Cardiovascular Research Institute (FCVRI), Northwestern University, Chicago, IL (K.T.S., M.S., R.W., H.C.C., A.K., T.S., C.K., T.L., H.A.).
authors.forename: Rongxue
authors.initials: R
authors.lastname: Wu
authors.affiliation: Feinberg Cardiovascular Research Institute (FCVRI), Northwestern University, Chicago, IL (K.T.S., M.S., R.W., H.C.C., A.K., T.S., C.K., T.L., H.A.).
authors.forename: Hsiang-Chun
authors.initials: HC
authors.lastname: Chang
authors.affiliation: Feinberg Cardiovascular Research Institute (FCVRI), Northwestern University, Chicago, IL (K.T.S., M.S., R.W., H.C.C., A.K., T.S., C.K., T.L., H.A.).
authors.forename: Arineh
authors.initials: A
authors.lastname: Khechaduri
authors.affiliation: Feinberg Cardiovascular Research Institute (FCVRI), Northwestern University, Chicago, IL (K.T.S., M.S., R.W., H.C.C., A.K., T.S., C.K., T.L., H.A.).
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Sato
authors.affiliation: Feinberg Cardiovascular Research Institute (FCVRI), Northwestern University, Chicago, IL (K.T.S., M.S., R.W., H.C.C., A.K., T.S., C.K., T.L., H.A.).
authors.forename: Christine
authors.initials: C
authors.lastname: Kamide
authors.affiliation: Feinberg Cardiovascular Research Institute (FCVRI), Northwestern University, Chicago, IL (K.T.S., M.S., R.W., H.C.C., A.K., T.S., C.K., T.L., H.A.).
authors.forename: Ting
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH (S.V.N.P.).
authors.forename: Sathyamangla V
authors.initials: SV
authors.lastname: Naga Prasad
authors.affiliation: Feinberg Cardiovascular Research Institute (FCVRI), Northwestern University, Chicago, IL (K.T.S., M.S., R.W., H.C.C., A.K., T.S., C.K., T.L., H.A.).
authors.forename: Hossein
authors.initials: H
authors.lastname: Ardehali
mesh_terms: D000624:5-Aminolevulinate Synthetase / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D016923:Cell Death; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004790:Enzyme Induction; D006333:Heart Failure / Q000378:metabolism; D006418:Heme / Q000378:metabolism*; D006801:Humans; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000378:metabolism; D009203:Myocardial Infarction / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D034622:RNA Interference; D015398:Signal Transduction; D014162:Transfection; D015854:Up-Regulation
chemical_list: D000975:Antioxidants; D006418:Heme; D000624:5-Aminolevulinate Synthetase; C480079:ALAS2 protein, human
keywords: apoptosis; heart failure; iron; metabolism; myocardial infarction