ArticlePloS one2014
Chymase mediates injury and mitochondrial damage in cardiomyocytes during acute ischemia/reperfusion in the dog.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 44 citations in OpenAlex.
- Engagement of chymase-positive mast cells in myocardial damage associated with COVID-19.Frontiers in cardiovascular medicine · 2026Article
- Sarcoplasmic reticulum-mitochondria microdomains: hugging and kissing in the heart.American journal of physiology. Cell physiology · 2025Review
- Nuclear receptor 4A1 Regulates Mitochondrial Homeostasis in Cardiac Post-Ischemic Injury by Controlling Mitochondrial Fission 1 Protein-Mediated Fragmentation and Parkin-Dependent Mitophagy.International journal of biological sciences · 2025Article
- Impact ofFrontiers in gastroenterology (Lausanne, Switzerland) · 2024Review
- Impact of early pericardial fluid chymase activation after cardiac surgery.Frontiers in cardiovascular medicine · 2023Article
- CLCF1 is up-regulated in renal ischemia reperfusion injury and may associate with FOXO3.Annals of translational medicine · 2022Article
- Carboxypeptidase A3 expression in canine mast cell tumors and tissue-resident mast cells.Veterinary pathology · 2022Article
- Adeno-associated virus 9 vector-mediated cardiac-selective expression of human secretory leukocyte protease inhibitor attenuates myocardial ischemia/reperfusion injury.Frontiers in cardiovascular medicine · 2022Article
- Post-Ischemic Treatment of Recombinant Human Secretory Leukocyte Protease Inhibitor (rhSLPI) Reduced Myocardial Ischemia/Reperfusion Injury.Biomedicines · 2021Article
- Clemastine Fumarate Attenuates Myocardial Ischemia Reperfusion Injury Through Inhibition of Mast Cell Degranulation.Frontiers in pharmacology · 2021Article
- Reduced Left Atrial Emptying Fraction and Chymase Activation in Pathophysiology of Primary Mitral Regurgitation.JACC. Basic to translational science · 2020Article
- Deficiency of mouse mast cell protease 4 mitigates cardiac dysfunctions in mice after myocardium infarction.Biochimica et biophysica acta. Molecular basis of disease · 2019Article
- Chymase uptake by cardiomyocytes results in myosin degradation in cardiac volume overload.Heliyon · 2019Article
- The renin-angiotensin-aldosterone system and its suppression.Journal of veterinary internal medicine · 2019Review
- Mast Cells in Cardiac Fibrosis: New Insights Suggest Opportunities for Intervention.Frontiers in immunology · 2019Review
- Bromine inhalation mimics ischemia-reperfusion cardiomyocyte injury and calpain activation in rats.American journal of physiology. Heart and circulatory physiology · 2019Article
- Proteases in Pemphigoid Diseases.Frontiers in immunology · 2019Review
- Article
- Degranulation of gastrointestinal mast cells contributes to hepatic ischemia-reperfusion injury in mice.Clinical science (London, England : 1979) · 2018Article
- Multifunctional Role of Chymase in Acute and Chronic Tissue Injury and Remodeling.Circulation research · 2018Review
Corrections and comments
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Authors and funding
13 authors at 3 institutions in 2 countries.
Funding
Abstract
Cardiac ischemia and reperfusion (I/R) injury occurs because the acute increase in oxidative/inflammatory stress during reperfusion culminates in the death of cardiomyocytes. Currently, there is no drug utilized clinically that attenuates I/R injury in patients. Previous studies have demonstrated degranulation of mast cell contents into the interstitium after I/R. Using a dog model of I/R, we tested the role of chymase, a mast cell protease, in cardiomyocyte injury using a specific oral chymase inhibitor (CI). 15 adult mongrel dogs had left anterior descending artery occlusion for 60 min and reperfusion for 100 minutes. 9 dogs received vehicle and 6 were pretreated with a specific CI. In vivo cardiac microdialysis demonstrated a 3-fold increase in interstitial fluid chymase activity in I/R region that was significantly decreased by CI. CI pretreatment significantly attenuated loss of laminin, focal adhesion complex disruption, and release of troponin I into the circulation. Microarray analysis identified an I/R induced 17-fold increase in nuclear receptor subfamily 4A1 (NR4A1) and significantly decreased by CI. NR4A1 normally resides in the nucleus but can induce cell death on migration to the cytoplasm. I/R caused significant increase in NR4A1 protein expression and cytoplasmic translocation, and mitochondrial degradation, which were decreased by CI. Immunohistochemistry also revealed a high concentration of chymase within cardiomyocytes after I/R. In vitro, chymase added to culture HL-1 cardiomyocytes entered the cytoplasm and nucleus in a dynamin-dependent fashion, and promoted cytoplasmic translocation of NR4A1 protein. shRNA knockdown of NR4A1 on pre-treatment of HL-1 cells with CI significantly decreased chymase-induced cell death and mitochondrial damage. These results suggest that the beneficial effects of an orally active CI during I/R are mediated in the cardiac interstitium as well as within the cardiomyocyte due to a heretofore-unrecognized chymase entry into cardiomyocytes.
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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.