ArticleThe Journal of pharmacology and experimental therapeutics2014
Histamine H4-receptors inhibit mast cell renin release in ischemia/reperfusion via protein kinase C ε-dependent aldehyde dehydrogenase type-2 activation.
Article in The Journal of pharmacology and experimental therapeutics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 27 citations in OpenAlex.
- Mast Cells in Cardiac Remodeling: Focus on the Right Ventricle.Journal of cardiovascular development and disease · 2024Review
- The mechanism and relevant mediators associated with neuronal apoptosis and potential therapeutic targets in subarachnoid hemorrhage.Neural regeneration research · 2023Review
- The Function of the Histamine H4 Receptor in Inflammatory and Inflammation-Associated Diseases of the Gut.International journal of molecular sciences · 2021Review
- The Roles of Cardiovascular HFrontiers in pharmacology · 2021Review
- Aldh2 Attenuates Stem Cell Factor/Kit-Dependent Signaling and Activation in Mast Cells.International journal of molecular sciences · 2019Article
- Activation of TGR5 with INT-777 attenuates oxidative stress and neuronal apoptosis via cAMP/PKCε/ALDH2 pathway after subarachnoid hemorrhage in rats.Free radical biology & medicine · 2019Article
- Regulation of Type 2 Immunity in Myocardial Infarction.Frontiers in immunology · 2019Review
- Alda‑1, an aldehyde dehydrogenase‑2 agonist, improves long‑term survival in rats with chronic heart failure following myocardial infarction.Molecular medicine reports · 2018Article
- A Retinoic AcidThe Journal of pharmacology and experimental therapeutics · 2018Article
- S1P receptor 1-Mediated Anti-Renin-Angiotensin System Cardioprotection: Pivotal Role of Mast Cell Aldehyde Dehydrogenase Type 2.The Journal of pharmacology and experimental therapeutics · 2017Article
- Pharmacological treatment options for mast cell activation disease.Naunyn-Schmiedeberg's archives of pharmacology · 2016Review
- International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors.Pharmacological reviews · 2015Review
- Selective cytoprotective effect of histamine on doxorubicin-induced hepatic and cardiac toxicity in animal models.Cell death discovery · 2015Article
- E-NTPDase1/CD39 modulates renin release from heart mast cells during ischemia/reperfusion: a novel cardioprotective role.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2015Article
- Precision Medicine Considerations for the Management of Heart Disease and Stroke in East Asians.Cardiology plusArticle
Corrections and comments
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Authors and funding
9 authors at 1 institution in 2 countries.
Funding
Abstract
Renin released by ischemia/reperfusion (I/R) from cardiac mast cells (MCs) activates a local renin-angiotensin system (RAS) causing arrhythmic dysfunction. Ischemic preconditioning (IPC) inhibits MC renin release and consequent activation of this local RAS. We postulated that MC histamine H4-receptors (H4Rs), being Gαi/o-coupled, might activate a protein kinase C isotype-ε (PKCε)-aldehyde dehydrogenase type-2 (ALDH2) cascade, ultimately eliminating MC-degranulating and renin-releasing effects of aldehydes formed in I/R and associated arrhythmias. We tested this hypothesis in ex vivo hearts, human mastocytoma cells, and bone marrow-derived MCs from wild-type and H4R knockout mice. We found that activation of MC H4Rs mimics the cardioprotective anti-RAS effects of IPC and that protection depends on the sequential activation of PKCε and ALDH2 in MCs, reducing aldehyde-induced MC degranulation and renin release and alleviating reperfusion arrhythmias. These cardioprotective effects are mimicked by selective H4R agonists and disappear when H4Rs are pharmacologically blocked or genetically deleted. Our results uncover a novel cardioprotective pathway in I/R, whereby activation of H4Rs on the MC membrane, possibly by MC-derived histamine, leads sequentially to PKCε and ALDH2 activation, reduction of toxic aldehyde-induced MC renin release, prevention of RAS activation, reduction of norepinephrine release, and ultimately to alleviation of reperfusion arrhythmias. This newly discovered protective pathway suggests that MC H4Rs may represent a new pharmacologic and therapeutic target for the direct alleviation of RAS-induced cardiac dysfunctions, including ischemic heart disease and congestive 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.