ArticleCardiovascular drugs and therapy2024
Levosimendan Reverses Cardiac Malfunction and Cardiomyocyte Ferroptosis During Heart Failure with Preserved Ejection Fraction via Connexin 43 Signaling Activation.
Article in Cardiovascular drugs and therapy, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 27 citations in OpenAlex.
- The Regulatory Landscape of Ferroptosis and Iron Homeostasis: Pathophysiological Mechanisms and Therapeutic Horizons in Cardiovascular Disease.Drug design, development and therapy · 2026Review
- A Single-Cell Transcriptomic Atlas Elucidates a Microglial Gene Signature Linking Ferroptosis to Mitochondrial Dysfunction in Epilepsy.Journal of inflammation research · 2026Article
- Levosimendan ameliorates cardiomyocyte injury and mitochondrial dysfunction in an Nrf2-dependent manner in mice with sepsis-induced cardiomyopathy.Acta biochimica et biophysica Sinica · 2025Article
- Novel Drug Targets in Diastolic Heart Disease.International journal of molecular sciences · 2025Review
- Overexpression of Cx43: Is It an Effective Approach for the Treatment of Cardiovascular Diseases?Biomolecules · 2025Review
- Short-Term Oral Administration of the Porcupine Inhibitor, Wnt-c59, Improves the Structural and Functional Features of Experimental HFpEF.Pharmacology research & perspectives · 2025Article
- Ferroptosis: The Pivotal Link in Cardiovascular Diseases Pathogenesis and Therapy.International journal of general medicine · 2025Review
- The Role of Programmed Types of Cell Death in Pathogenesis of Heart Failure with Preserved Ejection Fraction.International journal of molecular sciences · 2024Review
- Novel insights into the pathobiology of pulmonary hypertension in heart failure with preserved ejection fraction.American journal of physiology. Heart and circulatory physiology · 2024Review
- Levosimendan and Dobutamin Attenuate LPS-Induced Inflammation in Microglia by Inhibiting the NF-κB Pathway and NLRP3 Inflammasome Activation via Nrf2/HO-1 Signalling.Biomedicines · 2024Article
- Research advances on molecular mechanism and natural product therapy of iron metabolism in heart failure.European journal of medical research · 2024Review
- Combination decoction of Astragalus mongholicus andFrontiers in pharmacology · 2024Article
- Ferroptosis in diabetic cardiomyopathy: from its mechanisms to therapeutic strategies.Frontiers in endocrinology · 2024Review
- Insights into the Interaction of Heart Failure with Preserved Ejection Fraction and Sleep-Disordered Breathing.Biomedicines · 2023Review
- Exploring a new mechanism between lactate and VSMC calcification: PARP1/POLG/UCP2 signaling pathway and imbalance of mitochondrial homeostasis.Cell death & disease · 2023Article
- Development of heart failure with preserved ejection fraction is independent of eosinophils in a preclinical model.Immunity, inflammation and disease · 2023Article
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
purposeIn recent decades, the occurrence of heart failure with preserved ejection fraction (HFpEF) has outweighed that of heart failure with reduced ejection fraction by degrees, but few drugs have been demonstrated to improve long-term clinical outcomes in patients with HFpEF. Levosimendan, a calcium-sensitizing cardiotonic agent, improves decompensated heart failure clinically. However, the anti-HFpEF activities of levosimendan and underlying molecular mechanisms are unclear.
methodsIn this study, a double-hit HFpEF C57BL/6N mouse model was established, and levosimendan (3 mg/kg/week) was administered to HFpEF mice aged 13 to 17 weeks. Different biological experimental techniques were used to verify the protective effects of levosimendan against HFpEF.
resultsAfter four weeks of drug treatment, left ventricular diastolic dysfunction, cardiac hypertrophy, pulmonary congestion, and exercise exhaustion were significantly alleviated. Junction proteins in the endothelial barrier and between cardiomyocytes were also improved by levosimendan. Among the gap junction channel proteins, connexin 43, which was especially highly expressed in cardiomyocytes, mediated mitochondrial protection. Furthermore, levosimendan reversed mitochondrial malfunction in HFpEF mice, as evidenced by increased mitofilin and decreased ROS, superoxide anion, NOX4, and cytochrome C levels. Interestingly, after levosimendan administration, myocardial tissue from HFpEF mice showed restricted ferroptosis, indicated by an increased GSH/GSSG ratio; upregulated GPX4, xCT, and FSP-1 expression; and reduced intracellular ferrous ion, MDA, and 4-HNE levels.
conclusionRegular long-term levosimendan administration can benefit cardiac function in a mouse model of HFpEF with metabolic syndromes (namely, obesity and hypertension) by activating connexin 43-mediated mitochondrial protection and sequential ferroptosis inhibition in 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 Socratic graph.