ArticleJournal of the American Heart Association2015
Increased Heme Levels in the Heart Lead to Exacerbated Ischemic Injury.
Article in Journal of the American Heart Association, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers, 1 of them a synthesis that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
41 citing papers in PubMed, 1 synthesis or guideline pooled it, 56 citations in OpenAlex.
- Pooled it
- Effects of prosthetic heart valve-associated subclinical intravascular hemolysis on endothelium and cardiovascular system: a retrospective cohort study.Heart and vessels · 2026Article
- Pregnancy precipitates metabolic imbalance and accelerates death in an animal model of mitochondrial cardiomyopathy.Molecular metabolism · 2026Article
- Night shift work, dietary patterns, and coronary heart disease.European journal of epidemiology · 2026Article
- Integrated Bioinformatics Analysis Revealing that the NSDHL Gene Might Be Associated with the Progression of Western HFD/SW-Induced Hepatocellular CarcinomaEndocrine, metabolic & immune disorders drug targets · 2026Article
- Biomimetic ferritin nanocages for synergistic co-delivery of metformin and rapamycin restore neurodevelopmental homeostasis in autism spectrum disorders.Journal of nanobiotechnology · 2025Article
- The role of redox-active iron, copper, manganese, and redox-inactive zinc in toxicity, oxidative stress, and human diseases.EXCLI journal · 2025Review
- 25-Hydroxycholecalciferol Improves Cardiac Metabolic Adaption, Mitochondrial Biogenetics, and Redox Status to Ameliorate Pathological Remodeling and Functional Failure in Obese Chickens.Antioxidants (Basel, Switzerland) · 2024Article
- IL-6 inhibition prevents costimulation blockade-resistant allograft rejection in T cell-depleted recipients by promoting intragraft immune regulation in mice.Nature communications · 2024Article
- Article
- β-blockers and metabolic modulation: unraveling the complex interplay with glucose metabolism, inflammation and oxidative stress.Frontiers in pharmacology · 2024Review
- Targeting Ferroptosis: A Novel Strategy for the Treatment of Atherosclerosis.Mini reviews in medicinal chemistry · 2024Review
- Iron Dyshomeostasis and Mitochondrial Function in the Failing Heart: A Review of the Literature.American journal of cardiovascular drugs : drugs, devices, and other interventions · 2024Review
- Role of Erythropoiesis-Stimulating Agents in Cardiovascular Protection in CKD Patients: Reappraisal of Their Impact and Mechanisms.Cardiovascular drugs and therapy · 2023Review
- METTL3-modified lncRNA-SNHG8 binds to PTBP1 to regulate ALAS2 expression to increase oxidative stress and promote myocardial infarction.Molecular and cellular biochemistry · 2023Article
- Iron Metabolism in Cardiovascular Disease: Physiology, Mechanisms, and Therapeutic Targets.Circulation research · 2023Review
- Haem Iron Intake Is Associated with Increased Major Adverse Cardiovascular Events, All-Cause Mortality, Congestive Cardiac Failure, and Coronary Revascularisation in Older Men: The Concord Health and Ageing in Men Project.The journal of nutrition, health & aging · 2023Article
- ZFP36L2 suppresses mTORc1 through a P53-dependent pathway to prevent peripartum cardiomyopathy in mice.The Journal of clinical investigation · 2022Article
- Joint efficacy of the three biomarkers SNCA, GYPB and HBG1 for atrial fibrillation and stroke: Analysis via the support vector machine neural network.Journal of cellular and molecular medicine · 2022Article
- Iron Deficiency in Heart Failure: Mechanisms and Pathophysiology.Journal of clinical medicine · 2021Review
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundHeme 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. METHODS AND
resultsWe 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.
conclusionsHeme 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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.