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Vaseghi M, van Weperen V, Hoang J, Jani N, Atmani K, Chan C, Cao K, Avathi S, Lokhandwala Z, Emamimeybodi M. Sympathetic nociceptive afferent signaling drives the chronic structural and functional autonomic remodeling after myocardial infarction. RESEARCH SQUARE 2025:rs.3.rs-6247307. [PMID: 40235500 PMCID: PMC11998784 DOI: 10.21203/rs.3.rs-6247307/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/17/2025]
Abstract
After myocardial infarction (MI), pathological autonomic remodeling, including vagal dysfunction and sympathoexcitation, occurs and predisposes to ventricular arrhythmias (VT/VF). The underlying factors that drive this remodeling, including the observed neuroinflammation and glial activation, remain unknown. We hypothesized that sympathetic nociceptive afferents underlie this remodeling post-MI. Epidural resiniferatoxin (RTX, to ablate sympathetic cardiac afferent neurons) vs. saline was administered in pigs prior to MI and autonomic and electrophysiological effects assessed four to six weeks post-infarction. Acute effects of afferent ablation after chronic MI were also assessed in a separate group of animals. Baroreflex sensitivity and vagal tone, as measured by parasympathetic neuronal activity and cardiac nociceptive responses, were improved in infarcted animals which received epidural RTX prior to MI. These animals also demonstrated reduced spinal cord inflammation and glial activation, downregulation of circulating stress and inflammatory pathways, and stabilization of electrophysiological parameters, with reduced VT/VF-inducibility. Epidural RTX after chronic MI also acutely restored vagal function and decreased VT/VF. These data suggest that cardiac spinal nociceptive afferents directly contribute to VT/VF susceptibility and MI-induced autonomic remodeling, including oxidative stress, inflammation, glial activation, and reduced vagal function, providing novel insights into the causal role of these afferents in driving sympathovagal imbalance after MI.
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van Weperen V, Hoang JD, Jani N, Atmani K, Chan CA, Cao K, Avasthi S, Lokhandwala ZA, Emamimeybodi M, Vaseghi M. Sympathetic nociceptive afferent signaling drives the chronic structural and functional autonomic remodeling after myocardial infarction. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.28.645120. [PMID: 40196476 PMCID: PMC11974784 DOI: 10.1101/2025.03.28.645120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/09/2025]
Abstract
After myocardial infarction (MI), pathological autonomic remodeling, including vagal dysfunction and sympathoexcitation, occurs and predisposes to ventricular arrhythmias (VT/VF). The underlying factors that drive this remodeling, including the observed neuroinflammation and glial activation, remain unknown. We hypothesized that sympathetic nociceptive afferents underlie this remodeling post-MI. Epidural resiniferatoxin (RTX, to ablate sympathetic cardiac afferent neurons) vs. saline was administered in pigs prior to MI and autonomic and electrophysiological effects assessed four to six weeks post-infarction. Acute effects of afferent ablation after chronic MI were also assessed in a separate group of animals. Baroreflex sensitivity and vagal tone, as measured by parasympathetic neuronal activity and cardiac nociceptive responses, were improved in infarcted animals which received epidural RTX prior to MI. These animals also demonstrated reduced spinal cord inflammation and glial activation, downregulation of circulating stress and inflammatory pathways, and stabilization of electrophysiological parameters, with reduced VT/VF-inducibility. Epidural RTX after chronic MI also acutely restored vagal function and decreased VT/VF. These data suggest that cardiac spinal nociceptive afferents directly contribute to VT/VF susceptibility and MI-induced autonomic remodeling, including oxidative stress, inflammation, glial activation, and reduced vagal function, providing novel insights into the causal role of these afferents in driving sympathovagal imbalance after MI.
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McLean E, Roo CD, Maag A, Coble M, Cano J, Liu R. ERK1/2 Inhibition Alleviates Diabetic Cardiomyopathy by Suppressing Fatty Acid Metabolism. FRONT BIOSCI-LANDMRK 2025; 30:26700. [PMID: 39862096 DOI: 10.31083/fbl26700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 11/26/2024] [Accepted: 12/02/2024] [Indexed: 01/27/2025]
Abstract
BACKGROUND Diabetes mellitus is associated with morphological and functional impairment of the heart primarily due to lipid toxicity caused by increased fatty acid metabolism. Extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) have been implicated in the metabolism of fatty acids in the liver and skeletal muscles. However, their role in the heart in diabetes remains unclear. In this study, we tested our hypothesis that pharmacological inhibition of ERK1/2 alleviates cardiac remodeling in diabetic mice through a reduction in fatty acid metabolism. METHODS ERK1/2 phosphorylation in diabetes was determined both in vitro and in vivo. H9C2 cells were subjected to high glucose, high palmitic acid, or both high glucose and palmitic acid. db/db and streptozotocin (STZ)-induced diabetic mice were analyzed for ERK1/2 phosphorylation levels as well as the effects of U0126 treatment on cardiac remodeling. Administration of STZ and U0126 in mice was performed via intraperitoneal injection. Blood glucose levels in mice were measured using a glucometer. Mouse heart total RNAs were purified for reverse transcription. Real-time polymerase chain reaction (PCR) analysis of the messenger ribonucleic acid (mRNA) expression was performed for hypertrophy (ANF, BNP, and βMHC), fibrosis (Col3α1), and fatty acid metabolism genes (PPARα, CPT1A, and FACS). Interstitial fibrosis of the myocardium was analyzed using Masson's trichrome staining of the paraffin-embedded tissues. RESULTS ERK1/2 phosphorylation was significantly increased in diabetic conditions. Inhibition of ERK1/2 by U0126 in both streptozotocin-induced diabetic mice and db/db mice resulted in a significant reduction in the expression of genes associated with hypertrophy and fibrosis. In contrast, elevated phosphorylation of ERK1/2 in Dusp6/8 knockout (DKO) mice resulted in fibrosis. Mechanistically, ERK1/2 activation enhanced the expression of fatty acid metabolism genes PPARα, CPT1A, and FACS in the heart, which was reversed by U0126 treatment. CONCLUSION ERK1/2 are potential therapeutic targets for diabetic cardiomyopathy by modulating fatty acid metabolism in the heart.
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Affiliation(s)
- Erin McLean
- Department of Biomedical Sciences, Grand Valley State University, Allendale, MI 49401, USA
| | - Caroline De Roo
- Department of Biomedical Sciences, Grand Valley State University, Allendale, MI 49401, USA
| | - Annabel Maag
- Department of Biomedical Sciences, Grand Valley State University, Allendale, MI 49401, USA
| | - Megan Coble
- Department of Biomedical Sciences, Grand Valley State University, Allendale, MI 49401, USA
| | - Jefferson Cano
- Department of Biomedical Sciences, Grand Valley State University, Allendale, MI 49401, USA
| | - Ruijie Liu
- Department of Biomedical Sciences, Grand Valley State University, Allendale, MI 49401, USA
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Al Ali HS, Rodrigo GC, Lambert DG. Signalling pathways involved in urotensin II induced ventricular myocyte hypertrophy. PLoS One 2025; 20:e0313119. [PMID: 39820183 PMCID: PMC11737703 DOI: 10.1371/journal.pone.0313119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Accepted: 10/20/2024] [Indexed: 01/19/2025] Open
Abstract
Sustained pathologic myocardial hypertrophy can result in heart failure(HF); a significant health issue affecting a large section of the population worldwide. In HF there is a marked elevation in circulating levels of the peptide urotensin II(UII) but it is unclear whether this is a result of hypertrophy or whether the high levels contribute to the development of hypertrophy. The aim of this study is to investigate a role of UII and its receptor UT in the development of cardiac hypertrophy and the signalling molecules involved. Ventricular myocytes isolated from adult rat hearts were treated with 200nM UII for 48hours and hypertrophy was quantified from measurements of length/width (L/W) ratio. UII resulted in a change in L/W ratio from 4.53±0.10 to 3.99±0.06; (p<0.0001) after 48hours. The response is reversed by the UT-antagonist SB657510 (1μM). UT receptor activation by UII resulted in the activation of ERK1/2, p38 and CaMKII signalling pathways measured by Western blotting; these are involved in the induction of hypertrophy. JNK was not involved. Moreover, ERK1/2, P38 and CaMKII inhibitors completely blocked UII-induced hypertrophy. Sarcoplasmic reticulum (SR) Ca2+-leak was investigated in isolated myocytes. There was no significant increase in SR Ca2+-leak. Our results suggest that activation of MAPK and CaMKII signalling pathways are involved in the hypertrophic response to UII. Collectively our data suggest that increased circulating UII may contribute to the development of left ventricular hypertrophy and pharmacological inhibition of the UII/UT receptor system may prove beneficial in reducing adverse remodeling and alleviating contractile dysfunction in heart disease.
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Affiliation(s)
- Hadeel S. Al Ali
- Department of Cardiovascular Sciences, Clinical Sciences Wing, Glenfield Hospital, University of Leicester, Leicester, United Kingdom
- Department of Physiology, Al-Zahraa College of Medicine, University of Basrah, Basrah, Iraq
| | - Glenn C. Rodrigo
- Department of Cardiovascular Sciences, Clinical Sciences Wing, Glenfield Hospital, University of Leicester, Leicester, United Kingdom
| | - David G. Lambert
- Department of Cardiovascular Sciences, Anaesthesia, Critical Care and Pain Management, University of Leicester, Leicester, United Kingdom
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Sahu Y, Jamadade P, Ch Maharana K, Singh S. Role of mitochondrial homeostasis in D-galactose-induced cardiovascular ageing from bench to bedside. Mitochondrion 2024; 78:101923. [PMID: 38925493 DOI: 10.1016/j.mito.2024.101923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 06/11/2024] [Accepted: 06/15/2024] [Indexed: 06/28/2024]
Abstract
Ageing is an inevitable phenomenon which affects the cellular to the organism level in the progression of the time. Oxidative stress and inflammation are now widely regarded as the key processes involved in the aging process, which may then cause significant harm to mitochondrial DNA, leading to apoptosis. Normal circulatory function is a significant predictor of disease-free life expectancy. Indeed, disorders affecting the cardiovascular system, which are becoming more common, are the primary cause of worldwide morbidity, disability, and mortality. Cardiovascular aging may precede or possibly underpin overall, age-related health decline. Numerous studies have foundmitochondrial mechanistc approachplays a vital role in the in the onset and development of aging. The D-galactose (D-gal)-induced aging model is well recognized and commonly used in the aging study. In this review we redeposit the association of the previous and current studies on mitochondrial homeostasis and its underlying mechanisms in D-galactose cardiovascular ageing. Further we focus the novel and the treatment strategies to combat the major complication leading to the cardiovascular ageing.
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Affiliation(s)
- Yogita Sahu
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hajipur, Vaishali, Bihar, India
| | - Pratiksha Jamadade
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hajipur, Vaishali, Bihar, India
| | - Krushna Ch Maharana
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hajipur, Vaishali, Bihar, India
| | - Sanjiv Singh
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hajipur, Vaishali, Bihar, India.
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Pedersen S, Nielsen MØ, Donia M, Svane IM, Zerahn B, Ellebaek E. Real-World Cardiotoxicity in Metastatic Melanoma Patients Treated with Encorafenib and Binimetinib. Cancers (Basel) 2024; 16:2945. [PMID: 39272803 PMCID: PMC11394091 DOI: 10.3390/cancers16172945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 08/16/2024] [Accepted: 08/23/2024] [Indexed: 09/15/2024] Open
Abstract
Modern therapies targeting the BRAF gene mutation in advanced melanoma have significantly improved patient outcomes but pose cardiovascular risks. This retrospective study in Eastern Denmark (2019-2022) assessed 108 melanoma patients treated with encorafenib and binimetinib. Patients were monitored for heart function using multigated acquisition (MUGA) scans. The study defined major cardiotoxicity as a decline in left ventricular ejection fraction (LVEF) by more than 10 percentage points to below 50%, and minor cardiotoxicity as a decrease in LVEF by more than 15 points but remaining above 50%. Results showed that 19 patients (18%) developed minor cardiotoxicity and were asymptomatic, while 7 (6%) experienced major cardiotoxicity, with two requiring intervention. Notably, no significant declines in LVEF were observed after six months of treatment. The study concluded that significant cardiotoxicity occurred in 6% of cases, mostly asymptomatic and reversible, and suggests that monitoring LVEF could potentially be reduced after 6-9 months if no early signs of cardiotoxicity are detected. This provides valuable insights into the cardiac safety of these treatments in real-world settings.
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Affiliation(s)
- Sidsel Pedersen
- Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev and Gentofte, 2730 Herlev, Denmark
| | - Marc Østergaard Nielsen
- Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital, Herlev and Gentofte, 2730 Herlev, Denmark
| | - Marco Donia
- Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev and Gentofte, 2730 Herlev, Denmark
| | - Inge Marie Svane
- Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev and Gentofte, 2730 Herlev, Denmark
| | - Bo Zerahn
- Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital, Herlev and Gentofte, 2730 Herlev, Denmark
| | - Eva Ellebaek
- Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev and Gentofte, 2730 Herlev, Denmark
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Bobis-Wozowicz S, Paw M, Sarna M, Kędracka-Krok S, Nit K, Błażowska N, Dobosz A, Hammad R, Cathomen T, Zuba-Surma E, Tyszka-Czochara M, Madeja Z. Hypoxic extracellular vesicles from hiPSCs protect cardiomyocytes from oxidative damage by transferring antioxidant proteins and enhancing Akt/Erk/NRF2 signaling. Cell Commun Signal 2024; 22:356. [PMID: 38982464 PMCID: PMC11232324 DOI: 10.1186/s12964-024-01722-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Accepted: 06/21/2024] [Indexed: 07/11/2024] Open
Abstract
BACKGROUND Stem cell-derived extracellular vesicles (EVs) are an emerging class of therapeutics with excellent biocompatibility, bioactivity and pro-regenerative capacity. One of the potential targets for EV-based medicines are cardiovascular diseases (CVD). In this work we used EVs derived from human induced pluripotent stem cells (hiPSCs; hiPS-EVs) cultured under different oxygen concentrations (21, 5 and 3% O2) to dissect the molecular mechanisms responsible for cardioprotection. METHODS EVs were isolated by ultrafiltration combined with size exclusion chromatography (UF + SEC), followed by characterization by nanoparticle tracking analysis, atomic force microscopy (AFM) and Western blot methods. Liquid chromatography and tandem mass spectrometry coupled with bioinformatic analyses were used to identify differentially enriched proteins in various oxygen conditions. We directly compared the cardioprotective effects of these EVs in an oxygen-glucose deprivation/reoxygenation (OGD/R) model of cardiomyocyte (CM) injury. Using advanced molecular biology, fluorescence microscopy, atomic force spectroscopy and bioinformatics techniques, we investigated intracellular signaling pathways involved in the regulation of cell survival, apoptosis and antioxidant response. The direct effect of EVs on NRF2-regulated signaling was evaluated in CMs following NRF2 inhibition with ML385. RESULTS We demonstrate that hiPS-EVs derived from physiological hypoxia at 5% O2 (EV-H5) exert enhanced cytoprotective function towards damaged CMs compared to EVs derived from other tested oxygen conditions (normoxia; EV-N and hypoxia 3% O2; EV-H3). This resulted from higher phosphorylation rates of Akt kinase in the recipient cells after transfer, modulation of AMPK activity and reduced apoptosis. Furthermore, we provide direct evidence for improved calcium signaling and sustained contractility in CMs treated with EV-H5 using AFM measurements. Mechanistically, our mass spectrometry and bioinformatics analyses revealed differentially enriched proteins in EV-H5 associated with the antioxidant pathway regulated by NRF2. In this regard, EV-H5 increased the nuclear translocation of NRF2 protein and enhanced its transcription in CMs upon OGD/R. In contrast, inhibition of NRF2 with ML385 abolished the protective effect of EVs on CMs. CONCLUSIONS In this work, we demonstrate a superior cardioprotective function of EV-H5 compared to EV-N and EV-H3. Such EVs were most effective in restoring redox balance in stressed CMs, preserving their contractile function and preventing cell death. Our data support the potential use of hiPS-EVs derived from physiological hypoxia, as cell-free therapeutics with regenerative properties for the treatment of cardiac diseases.
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Affiliation(s)
- Sylwia Bobis-Wozowicz
- Faculty of Biochemistry, Biophysics and Biotechnology, Department of Cell Biology, Jagiellonian University, Kraków, Poland.
| | - Milena Paw
- Faculty of Biochemistry, Biophysics and Biotechnology, Department of Cell Biology, Jagiellonian University, Kraków, Poland
| | - Michał Sarna
- Faculty of Biochemistry, Biophysics and Biotechnology, Department of Biophysics, Jagiellonian University, Krakow, Poland
| | - Sylwia Kędracka-Krok
- Faculty of Biochemistry, Biophysics and Biotechnology, Department of Physical Biochemistry, Jagiellonian University, Krakow, Poland
| | - Kinga Nit
- Faculty of Biochemistry, Biophysics and Biotechnology, Department of Cell Biology, Jagiellonian University, Kraków, Poland
| | - Natalia Błażowska
- Faculty of Biochemistry, Biophysics and Biotechnology, Department of Cell Biology, Jagiellonian University, Kraków, Poland
| | - Anna Dobosz
- Faculty of Biochemistry, Biophysics and Biotechnology, Department of Cell Biology, Jagiellonian University, Kraków, Poland
| | - Ruba Hammad
- Freiburg iPS Core Facility, Institute for Transfusion Medicine and Gene Therapy, Medical Center- University of Freiburg, Freiburg, Germany
- Center for Chronic Immunodeficiency (CCI), University of Freiburg, Freiburg, Germany
| | - Toni Cathomen
- Freiburg iPS Core Facility, Institute for Transfusion Medicine and Gene Therapy, Medical Center- University of Freiburg, Freiburg, Germany
- Center for Chronic Immunodeficiency (CCI), University of Freiburg, Freiburg, Germany
| | - Ewa Zuba-Surma
- Faculty of Biochemistry, Biophysics and Biotechnology, Department of Cell Biology, Jagiellonian University, Kraków, Poland
| | - Małgorzata Tyszka-Czochara
- Faculty of Pharmacy, Department of Food Chemistry and Nutrition, Jagiellonian University Medical College, Kraków, Poland
| | - Zbigniew Madeja
- Faculty of Biochemistry, Biophysics and Biotechnology, Department of Cell Biology, Jagiellonian University, Kraków, Poland
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Strash N, DeLuca S, Janer Carattini GL, Chen Y, Wu T, Helfer A, Scherba J, Wang I, Jain M, Naseri R, Bursac N. Time-dependent effects of BRAF-V600E on cell cycling, metabolism, and function in engineered myocardium. SCIENCE ADVANCES 2024; 10:eadh2598. [PMID: 38266090 PMCID: PMC10807800 DOI: 10.1126/sciadv.adh2598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Accepted: 12/22/2023] [Indexed: 01/26/2024]
Abstract
Candidate cardiomyocyte (CM) mitogens such as those affecting the extracellular signal-regulated kinase (ERK) signaling pathway represent potential targets for functional heart regeneration. We explored whether activating ERK via a constitutively active mutant of B-raf proto-oncogene (BRAF), BRAF-V600E (caBRAF), can induce proproliferative effects in neonatal rat engineered cardiac tissues (ECTs). Sustained CM-specific caBRAF expression induced chronic ERK activation, substantial tissue growth, deficit in sarcomeres and contractile function, and tissue stiffening, all of which persisted for at least 4 weeks of culture. caBRAF-expressing CMs in ECTs exhibited broad transcriptomic changes, shift to glycolytic metabolism, loss of connexin-43, and a promigratory phenotype. Transient, doxycycline-controlled caBRAF expression revealed that the induction of CM cycling is rapid and precedes functional decline, and the effects are reversible only with short-lived ERK activation. Together, direct activation of the BRAF kinase is sufficient to modulate CM cycling and functional phenotype, offering mechanistic insights into roles of ERK signaling in the context of cardiac development and regeneration.
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Affiliation(s)
| | - Sophia DeLuca
- Department of Cell Biology, Duke University, Durham NC, USA
| | | | - Yifan Chen
- Department of Biomedical Engineering, Duke University, Durham NC, USA
| | - Tianyu Wu
- Department of Biomedical Engineering, Duke University, Durham NC, USA
| | - Abbigail Helfer
- Department of Biomedical Engineering, Duke University, Durham NC, USA
| | - Jacob Scherba
- Department of Biomedical Engineering, Duke University, Durham NC, USA
| | - Isabella Wang
- Department of Biomedical Engineering, Duke University, Durham NC, USA
| | - Mehul Jain
- Department of Biomedical Engineering, Duke University, Durham NC, USA
| | - Ramona Naseri
- Department of Biomedical Engineering, Duke University, Durham NC, USA
| | - Nenad Bursac
- Department of Cell Biology, Duke University, Durham NC, USA
- Department of Biomedical Engineering, Duke University, Durham NC, USA
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Tian X, Yin S, Liu Z, Cao J, Liu X, Qiu Q. Elucidation of the Molecular Mechanism of Compound Danshen Dripping Pills against Angina Pectoris based on Network Pharmacology and Molecular Docking. Curr Pharm Des 2024; 30:1247-1264. [PMID: 38584551 DOI: 10.2174/0113816128287109240321074628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 02/29/2024] [Accepted: 03/05/2024] [Indexed: 04/09/2024]
Abstract
BACKGROUND Compound Danshen dripping pills (CDDP), a traditional Chinese medicine, has had an extensive application in the treatment of angina pectoris (AP) in China. However, research on the bioactive ingredients and underlying mechanisms of CDDP in AP remains unclear. OBJECTIVE In the present study, we explored the major chemical components and potential molecular mechanisms linked to the anti-angina effects of CDDP through the application of network pharmacology and molecular docking. METHODS The potential targets of active ingredients in CDDP were sourced from the Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) and the Swiss Target Prediction Database (STPD). Additionally, targets related to angina pectoris (AP) were retrieved from various databases, including Gene Cards, DisGeNET, Dis Genet, the Drug Bank database (DBD), and the Therapeutic Target Database (TDD). Protein- protein interaction networks were also established, and core targets were identified based on their topological significance. GO enrichment analysis and KEGG pathway analysis were conducted using the R software. Interactions between active ingredients and potential targets selected through the above process were investigated through molecular docking. RESULTS Seventy-six active ingredients were selected with the following criteria: OB ≥ 30%, DL ≥ 0.18. 383 targets of CDDP and 1488 targets on AP were gathered, respectively. Afterwards, 194 common targets of CDDP and anti-AP targets were defined, of which 12 were core targets. GO enrichment analysis indicated that CDDP acted on AP by response to lipopolysaccharide, regulating the reactive oxygen species and metal ion metabolism, and epithelial cell proliferation. In addition, KEGG enrichment analysis indicated that the signaling pathways were notably enriched in lipid and atherosclerosis, fluid shear stress and atherosclerosis, IL-17 signaling pathway, EGFR tyrosine kinase inhibitor resistance, PI3K-Akt signaling pathway, and TNF signaling pathway. Moreover, the molecular docking manifested excellent binding capacity between the active ingredients and targets on AP. CONCLUSION This study comprehensively illustrated the bioactive, potential targets, and molecular mechanisms of CDDP against AP, offering fresh perspectives into the molecular mechanisms of CDDP in preventing and treating AP.
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Affiliation(s)
- Xiaocui Tian
- Department of Pharmacy, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Shiqi Yin
- Department of Pharmacy, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
- School of Pharmaceutical Sciences, Capital Medical University, Beijing, China
| | - Zhiguang Liu
- Department of Pharmacy, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Jinglin Cao
- Department of Pharmacy, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Xinyu Liu
- Department of Pharmacy, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Qi Qiu
- Department of Pharmacy, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
- School of Pharmaceutical Sciences, Capital Medical University, Beijing, China
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10
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Li S, Gao K, Yao D. Comprehensive analysis of autophagy associated genes and immune infiltrates in cervical cancer. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2024; 27:813-824. [PMID: 38800011 PMCID: PMC11127083 DOI: 10.22038/ijbms.2024.74431.16168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Accepted: 11/26/2023] [Indexed: 05/29/2024]
Abstract
Objectives Cervical cancer (CC) is the most common gynecological malignant tumor and the fourth leading cause of cancer-related death in women. The progression of CC is significantly affected by autophagy. Our objective was to use bioinformatics analysis to explore the expression, prognostic significance, and immune infiltration of autophagy-related genes in CC. Materials and Methods We identified a set of autophagy-related differentially expressed genes (ARDEGs) from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. ARDEGs were further validated by The Human Protein Atlas (HPA), GSE52903, and GSE39001 dataset. Hub genes were found by the STRING network and Cytoscape. We performed Gene Set Enrichment Analysis (GSEA), Gene ontology analysis (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and immune infiltration analysis to further understand the functions of the hub genes. Kaplan-Meier (K-M) and receiver operating characteristic (ROC) were used to check the hub genes. Results A total of 10 up-regulated (CXCR4, BAX, SPHK1, EIF2AK2, TBK1, TNFSF10, ITGB4, CDKN2A, IL24, and BIRC5) and 19 down-regulated (PINK1, ATG16L2, ATG4D, IKBKE, MLST8, MAPK3, ERBB2, ULK3, TP53INP2, MTMR14, BNIP3, FOS, CCL2, FAS, CAPNS1, HSPB8, PTK6, FKBP1B , and DNAJB1) ARDEGs were identified. The ARDEGs were enriched in cell growth, apoptosis, human papillomavirus infection, and cytokine-mediated. Then, we found that low expression of MAPK3 was associated with poor prognosis in CC patients and was significantly enriched in immune pathways. In addition, the expression of MAPK3 was significantly positively correlated with the infiltration levels of macrophages, B cells, mast cell activation, and cancer-associated fibroblasts. Furthermore, MAPK3 was positively correlated with LGALS9, and negatively correlated with CTLA4 and CD40. Conclusion Our results show that MAPK3 can be used as a new prognostic biomarker to predict the prognosis of patients with CC.
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Affiliation(s)
- Shuzhen Li
- Department of Gynecologic Oncology, Guangxi Medical University Cancer Hospital Nanning, Guangxi Zhuang Autonomous Region 530021, PR China
| | - Kun Gao
- Department of Gynecologic Oncology, Guangxi Medical University Cancer Hospital Nanning, Guangxi Zhuang Autonomous Region 530021, PR China
| | - Desheng Yao
- Department of Gynecologic Oncology, Guangxi Medical University Cancer Hospital Nanning, Guangxi Zhuang Autonomous Region 530021, PR China
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11
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Kwok C, Nolan M. Cardiotoxicity of anti-cancer drugs: cellular mechanisms and clinical implications. Front Cardiovasc Med 2023; 10:1150569. [PMID: 37745115 PMCID: PMC10516301 DOI: 10.3389/fcvm.2023.1150569] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Accepted: 07/17/2023] [Indexed: 09/26/2023] Open
Abstract
Cardio-oncology is an emerging field that seeks to enhance quality of life and longevity of cancer survivors. It is pertinent for clinicians to understand the cellular mechanisms of prescribed therapies, as this contributes to robust understanding of complex treatments and off-target effects, improved communication with patients, and guides long term care with the goal to minimise or prevent cardiovascular complications. Our aim is to review the cellular mechanisms of cardiotoxicity involved in commonly used anti-cancer treatments and identify gaps in literature and strategies to mitigate cardiotoxicity effects and guide future research endeavours.
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Affiliation(s)
- Cecilia Kwok
- Department of Medicine, Western Health, Melbourne, VIC, Australia
| | - Mark Nolan
- Department of Medicine, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- Cardiovascular Imaging, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
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Golatkar V, Bhatt LK. mAKAPβ signalosome: A potential target for cardiac hypertrophy. Drug Dev Res 2023; 84:1072-1084. [PMID: 37203301 DOI: 10.1002/ddr.22081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 03/05/2023] [Accepted: 05/06/2023] [Indexed: 05/20/2023]
Abstract
Pathological cardiac hypertrophy is the result of a prolonged increase in the workload of the heart that activates various signaling pathways such as MAPK pathway, PKA-dependent cAMP signaling, and CaN-NFAT signaling pathway which further activates genes for cardiac remodeling. Various signalosomes are present in the heart that regulates the signaling of physiological and pathological cardiac hypertrophy. mAKAPβ is one such scaffold protein that regulates signaling pathways involved in promoting cardiac hypertrophy. It is present in the outer nuclear envelope of the cardiomyocytes, which provides specificity of the target toward the heart. In addition, nuclear translocation of signaling components and transcription factors such as MEF2D, NFATc, and HIF-1α is facilitated due to the localization of mAKAPβ near the nuclear envelope. These factors are required for activation of genes promoting cardiac remodeling. Downregulation of mAKAPβ improves cardiac function and attenuates cardiac hypertrophy which in turn prevents the development of heart failure. Unlike earlier therapies for heart failure, knockout or silencing of mAKAPβ is not associated with side effects because of its high specificity in the striated myocytes. Downregulating expression of mAKAPβ is a favorable therapeutic approach toward attenuating cardiac hypertrophy and hence preventing heart failure. This review discusses mAKAPβ signalosome as a potential target for cardiac hypertrophy intervention.
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Affiliation(s)
- Vaishnavi Golatkar
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Vile Parle (W), Mumbai, India
| | - Lokesh K Bhatt
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Vile Parle (W), Mumbai, India
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Qu WZ, Wang L, Chen JJ, Wang Y. Raf kinase inhibitor protein combined with phosphorylated extracellular signal-regulated kinase offers valuable prognosis in gastrointestinal stromal tumor. World J Gastroenterol 2023; 29:4200-4213. [PMID: 37475847 PMCID: PMC10354573 DOI: 10.3748/wjg.v29.i26.4200] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 05/20/2023] [Accepted: 06/02/2023] [Indexed: 07/10/2023] Open
Abstract
BACKGROUND Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Tyrosine kinase inhibitors, such as imatinib, have been used as first-line therapy for the treatment of GISTs. Although these drugs have achieved considerable efficacy in some patients, reports of resistance and recurrence have emerged. Extracellular signal-regulated kinase 1/2 (ERK1/2) protein, as a member of the mitogen-activated protein kinase (MAPK) family, is a core molecule of this signaling pathway. Nowadays, research reports on the important clinical and prognostic value of phosphorylated-ERK (P-ERK) and phosphorylated-MAPK/ERK kinase (P-MEK) proteins closely related to raf kinase inhibitor protein (RKIP) have gradually emerged in digestive tract tumors such as gastric cancer, colon cancer, and pancreatic cancer. However, literature on the expression of these downstream proteins combined with RKIP in GIST is scarce. This study will focus on this aspect and search for answers to the problem. AIM To detect the expression of RKIP, P-ERK, and P-MEK protein in GIST and to analyze their relationship with clinicopathological characteristics and prognosis of this disease. Try to establish a new prognosis evaluation model using RKIP and P-ERK in combination with analysis and its prognosis evaluation efficacy. METHODS The research object of our experiment was 66 pathologically diagnosed GIST patients with complete clinical and follow-up information. These patients received surgical treatment at China Medical University Affiliated Hospital from January 2015 to January 2020. Immunohistochemical method was used to detect the expression of RKIP, P-ERK, and P-MEK proteins in GIST tissue samples from these patients. Kaplan-Meier method was used to calculate the survival rate of 63 patients with complete follow-up data. A Nomogram was used to represent the new prognostic evaluation model. The Cox multivariate regression analysis was conducted separately for each set of risk evaluation factors, based on two risk classification systems [the new risk grade model vs the modified National Institutes of Health (NIH) 2008 risk classification system]. Receiver operating characteristic (ROC) curves were used for evaluating the accuracy and efficiency of the two prognostic evaluation systems. RESULTS In GIST tissues, RKIP protein showed positive expression in the cytoplasm and cell membrane, appearing as brownish-yellow or brown granules. The expression of RKIP was related to GIST tumor size, NIH grade, and mucosal invasion. P-ERK protein exhibited heterogeneous distribution in GIST cells, mainly in the cytoplasm, with occasional presence in the nucleus, and appeared as brownish-yellow granules, and the expression of P-ERK protein was associated with GIST tumor size, mitotic count, mucosal invasion, and NIH grade. Meanwhile, RKIP protein expression was negatively correlated with P-ERK expression. The results in COX multivariate regression analysis showed that RKIP protein expression was not an independent risk factor for tumor prognosis. However, RKIP combined with P-ERK protein expression were identified as independent risk factors for prognosis with statistical significance. Furthermore, we establish a new prognosis evaluation model using RKIP and P-ERK in combination and obtained the nomogram of the new prognosis evaluation model. ROC curve analysis also showed that the new evaluation model had better prognostic performance than the modified NIH 2008 risk classification system. CONCLUSION Our experimental results showed that the expression of RKIP and P-ERK proteins in GIST was associated with tumor size, NIH 2008 staging, and tumor invasion, and P-ERK expression was also related to mitotic count. The expression of the two proteins had a certain negative correlation. The combined expression of RKIP and P-ERK proteins can serve as an independent risk factor for predicting the prognosis of GIST patients. The new risk assessment model incorporating RKIP and P-ERK has superior evaluation efficacy and is worth further practical application to validate.
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Affiliation(s)
- Wen-Zhi Qu
- Department of General Surgery, The 4th Affiliated Hospital of China Medical University, Shenyang 110032, Liaoning Province, China
| | - Luan Wang
- Department of Emergency, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Juan-Juan Chen
- Department of Medical Service, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Yang Wang
- Department of General Surgery, The 4th Affiliated Hospital of China Medical University, Shenyang 110032, Liaoning Province, China
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Chaudhari U, Pohjolainen L, Ruskoaho H, Talman V. Genome-wide profiling of miRNA-gene regulatory networks in mouse postnatal heart development-implications for cardiac regeneration. Front Cardiovasc Med 2023; 10:1148618. [PMID: 37283582 PMCID: PMC10241105 DOI: 10.3389/fcvm.2023.1148618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 05/02/2023] [Indexed: 06/08/2023] Open
Abstract
Background After birth, mammalian cardiomyocytes substantially lose proliferative capacity with a concomitant switch from glycolytic to oxidative mitochondrial energy metabolism. Micro-RNAs (miRNAs) regulate gene expression and thus control various cellular processes. Their roles in the postnatal loss of cardiac regeneration are however still largely unclear. Here, we aimed to identify miRNA-gene regulatory networks in the neonatal heart to uncover role of miRNAs in regulation of cell cycle and metabolism. Methods and results We performed global miRNA expression profiling using total RNA extracted from mouse ventricular tissue samples collected on postnatal day 1 (P01), P04, P09, and P23. We used the miRWalk database to predict the potential target genes of differentially expressed miRNAs and our previously published mRNA transcriptomics data to identify verified target genes that showed a concomitant differential expression in the neonatal heart. We then analyzed the biological functions of the identified miRNA-gene regulatory networks using enriched Gene Ontology (GO) and KEGG pathway analyses. Altogether 46 miRNAs were differentially expressed in the distinct stages of neonatal heart development. For twenty miRNAs, up- or downregulation took place within the first 9 postnatal days thus correlating temporally with the loss of cardiac regeneration. Importantly, for several miRNAs, including miR-150-5p, miR-484, and miR-210-3p there are no previous reports about their role in cardiac development or disease. The miRNA-gene regulatory networks of upregulated miRNAs negatively regulated biological processes and KEGG pathways related to cell proliferation, while downregulated miRNAs positively regulated biological processes and KEGG pathways associated with activation of mitochondrial metabolism and developmental hypertrophic growth. Conclusion This study reports miRNAs and miRNA-gene regulatory networks with no previously described role in cardiac development or disease. These findings may help in elucidating regulatory mechanism of cardiac regeneration and in the development of regenerative therapies.
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Russo E, Bertolotto M, Zanetti V, Picciotto D, Esposito P, Carbone F, Montecucco F, Pontremoli R, Garibotto G, Viazzi F, Verzola D. Role of Uric Acid in Vascular Remodeling: Cytoskeleton Changes and Migration in VSMCs. Int J Mol Sci 2023; 24:2960. [PMID: 36769281 PMCID: PMC9917405 DOI: 10.3390/ijms24032960] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Revised: 01/29/2023] [Accepted: 02/01/2023] [Indexed: 02/05/2023] Open
Abstract
The mechanisms by which hyperuricemia induces vascular dysfunction and contributes to cardiovascular disease are still debated. Phenotypic transition is a property of vascular smooth muscle cells (VSMCs) involved in organ damage. The aim of this study was to investigate the effects of uric acid (UA) on changes in the VSMC cytoskeleton, cell migration and the signals involved in these processes. MOVAS, a mouse VSMC line, was incubated with 6, 9 and 12 mg/dL of UA, angiotensin receptor blockers (ARBs), proteasome and MEK-inhibitors. Migration property was assessed in a micro-chemotaxis chamber and by phalloidin staining. Changes in cytoskeleton proteins (Smoothelin B (SMTB), alpha-Smooth Muscle Actin (αSMA), Smooth Muscle 22 Alpha (SM22α)), Atrogin-1 and MAPK activation were determined by Western blot, immunostaining and quantitative reverse transcription PCR. UA exposition modified SMT, αSMA and SM22α levels (p < 0.05) and significantly upregulated Atrogin-1 and MAPK activation. UA-treated VSMCs showed an increased migratory rate as compared to control cells (p < 0.001) and a re-arrangement of F-actin. Probenecid, proteasome inhibition and ARBs prevented the development of dysfunctional VSMC. This study shows, for the first time, that UA-induced cytoskeleton changes determine an increase in VSMC migratory rate, suggesting UA as a key player in vascular remodeling.
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Affiliation(s)
- Elisa Russo
- Nephrology and Dialysis Unit, San Luca Hospital, 55100 Lucca, Italy
| | - Maria Bertolotto
- Department of Internal Medicine, University of Genoa, 16132 Genoa, Italy
| | | | | | - Pasquale Esposito
- Department of Internal Medicine, University of Genoa, 16132 Genoa, Italy
- IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Federico Carbone
- Department of Internal Medicine, University of Genoa, 16132 Genoa, Italy
- IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Fabrizio Montecucco
- Department of Internal Medicine, University of Genoa, 16132 Genoa, Italy
- IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Roberto Pontremoli
- Department of Internal Medicine, University of Genoa, 16132 Genoa, Italy
- IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Giacomo Garibotto
- Department of Internal Medicine, University of Genoa, 16132 Genoa, Italy
| | - Francesca Viazzi
- Department of Internal Medicine, University of Genoa, 16132 Genoa, Italy
- IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Daniela Verzola
- Department of Internal Medicine, University of Genoa, 16132 Genoa, Italy
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Altara R, Booz G. Central role for BRAF in cardiac hypertrophy: rethinking the pathological-physiological divide. Clin Sci (Lond) 2023; 137:143-148. [PMID: 36651286 PMCID: PMC9873497 DOI: 10.1042/cs20220776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 12/23/2022] [Accepted: 01/05/2023] [Indexed: 01/19/2023]
Abstract
The RAF/MEK/ERK1/2 signaling cascade has been implicated in pathological cardiac hypertrophy downstream of some Gq-coupled receptors. The RAF family of kinases consists of three isoforms (ARAF, BRAF, and CRAF) and until recently most studies on this signaling pathway in the heart have focused on RAF1 (CRAF). In a recent issue of Clinical Science, Alharbi et al. utilized an inducible cardiac myocyte targeted knockout mouse model to define the role of BRAF in pathological versus physiological hypertrophy using angiotensin II and phenylephrine (PE) infusion, respectively. They reported that loss of BRAF attenuated both pathological cardiac hypertrophy and interstitial fibrosis. BRAF knockout decreased cardiac function with PE in male mice and enhanced both interstitial and perivascular cardiac fibrosis but had no effect on hypertrophy. In contrast, loss of BRAF attenuated physiological hypertrophy in female mice but had no effect on fibrosis or contractility. These observations extend those previously made by this group assessing the consequences of expressing an inducible activating mutant of BRAF in the heart and the benefit of enhancing RAF/MEK/ERK1/2 signaling by exploiting the 'RAF paradox'. Additional studies are needed to better define the role of BRAF under conditions reflective of chronic stress on the heart due to the biomechanical stimulation exerted by hypertension. In addition, the role of BRAF and its activation in overt heart failure remains to be established. Nevertheless, the new findings highlight the potential importance of additional signaling events, perhaps related to RAF1 or ERK1/2 activation, in shaping BRAF signaling in a sex- and context-dependent manner.
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Affiliation(s)
- Raffaele Altara
- Department of Pathology, School of Medicine, University of Mississippi Medical Center, Jackson, MS, U.S.A
- Department of Anatomy and Embryology, Maastricht University, Maastricht, The Netherlands
| | - George W. Booz
- Department of Pharmacology and Toxicology, School of Medicine, University of Mississippi Medical Center, Jackson, MS, U.S.A
- Correspondence: George W. Booz ()
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Britto-Borges T, Ludt A, Boileau E, Gjerga E, Marini F, Dieterich C. Magnetique: an interactive web application to explore transcriptome signatures of heart failure. J Transl Med 2022; 20:513. [DOI: 10.1186/s12967-022-03694-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 10/05/2022] [Accepted: 10/06/2022] [Indexed: 11/09/2022] Open
Abstract
Abstract
Background
Despite a recent increase in the number of RNA-seq datasets investigating heart failure (HF), accessibility and usability remain critical issues for medical researchers. We address the need for an intuitive and interactive web application to explore the transcriptional signatures of heart failure with this work.
Methods
We reanalysed the Myocardial Applied Genomics Network RNA-seq dataset, one of the largest publicly available datasets of left ventricular RNA-seq samples from patients with dilated (DCM) or hypertrophic (HCM) cardiomyopathy, as well as unmatched non-failing hearts (NFD) from organ donors and patient characteristics that allowed us to model confounding factors. We analyse differential gene expression, associated pathway signatures and reconstruct signaling networks based on inferred transcription factor activities through integer linear programming. We additionally focus, for the first time, on differential RNA transcript isoform usage (DTU) changes and predict RNA-binding protein (RBP) to target transcript interactions using a Global test approach. We report results for all pairwise comparisons (DCM, HCM, NFD).
Results
Focusing on the DCM versus HCM contrast (DCMvsHCM), we identified 201 differentially expressed genes, some of which can be clearly associated with changes in ERK1 and ERK2 signaling. Interestingly, the signs of the predicted activity for these two kinases have been inferred to be opposite to each other: In the DCMvsHCM contrast, we predict ERK1 to be consistently less activated in DCM while ERK2 was more activated in DCM. In the DCMvsHCM contrast, we identified 149 differently used transcripts. One of the top candidates is the O-linked N-acetylglucosamine (GlcNAc) transferase (OGT), which catalyzes a common post-translational modification known for its role in heart arrhythmias and heart hypertrophy. Moreover, we reconstruct RBP – target interaction networks and showcase the examples of CPEB1, which is differentially expressed in the DCMvsHCM contrast.
Conclusion
Magnetique (https://shiny.dieterichlab.org/app/magnetique) is the first online application to provide an interactive view of the HF transcriptome at the RNA isoform level and to include transcription factor signaling and RBP:RNA interaction networks. The source code for both the analyses (https://github.com/dieterich-lab/magnetiqueCode2022) and the web application (https://github.com/AnnekathrinSilvia/magnetique) is available to the public. We hope that our application will help users to uncover the molecular basis of heart failure.
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Chen YF, Wu KJ, Siao LR, Tsai HY. Trilinolein, a Natural Triacylglycerol, Protects Cerebral Ischemia through Inhibition of Neuronal Apoptosis and Ameliorates Intimal Hyperplasia via Attenuation of Migration and Modulation of Matrix Metalloproteinase-2 and RAS/MEK/ERK Signaling Pathway in VSMCs. Int J Mol Sci 2022; 23:12820. [PMID: 36361610 PMCID: PMC9658252 DOI: 10.3390/ijms232112820] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 10/02/2022] [Accepted: 10/20/2022] [Indexed: 09/11/2023] Open
Abstract
Cerebrovascular disease is one of the leading causes of disability and death worldwide, and seeking a potential treatment is essential. Trilinolein (TriL) is a natural triacylglycerol presented in several plants. The effects of TriL on cerebrovascular diseases such as cerebral ischemia and carotid stenosis have never been studied. Accordingly, we investigated the protection of TriL on cerebral ischemia/reperfusion (I/R) and vascular smooth muscle cell (VSMC) migration in vivo and in vitro. The cerebral infarction area, the intima to media area (I/M ratio), and proliferating cell nuclear antigen (PCNA)-staining of the carotid artery were measured. Platelet-derived growth factor (PDGF)-BB-stimulated A7r5 cell migration and potential mechanisms of TriL were investigated by wound healing, transwell, and Western blotting. TriL (50, 100, and 200 mg/kg, p.o.) reduced: the cerebral infarction area; neurological deficit; TUNEL-positive apoptosis; intimal hyperplasia; and PCNA-positive cells in rodents. TriL (5, 10, and 20 µM) significantly inhibited PDGF-BB-stimulated A7r5 cell migration and reduced matrix metalloproteinase-2 (MMP-2), Ras, MEK, and p-ERK protein levels in PDGF-BB-stimulated A7r5 cells. TriL is protective in models of I/R-induced brain injury, carotid artery ligation-induced intimal hyperplasia, and VSMC migration both in vivo and in vitro. TriL could be potentially efficacious in preventing cerebral ischemia and cerebrovascular diseases.
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Affiliation(s)
- Yuh-Fung Chen
- Department of Pharmacology, China Medical University, Taichung 404333, Taiwan
- Department of Pharmacy, China Medical University Hospital, Taichung 404332, Taiwan
| | - Kuo-Jen Wu
- Department of Pharmacology, China Medical University, Taichung 404333, Taiwan
| | - Lian-Ru Siao
- Department of Pharmacology, China Medical University, Taichung 404333, Taiwan
| | - Huei-Yann Tsai
- Department of Pharmacy, China Medical University Hospital, Taichung 404332, Taiwan
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Wang A, Li Z, Zhuo S, Gao F, Zhang H, Zhang Z, Ren G, Ma X. Mechanisms of Cardiorenal Protection With SGLT2 Inhibitors in Patients With T2DM Based on Network Pharmacology. Front Cardiovasc Med 2022; 9:857952. [PMID: 35677689 PMCID: PMC9169967 DOI: 10.3389/fcvm.2022.857952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 05/04/2022] [Indexed: 11/24/2022] Open
Abstract
Purpose Sodium-glucose cotransporter 2 (SGLT2) inhibitors have cardiorenal protective effects regardless of whether they are combined with type 2 diabetes mellitus, but their specific pharmacological mechanisms remain undetermined. Materials and Methods We used databases to obtain information on the disease targets of “Chronic Kidney Disease,” “Heart Failure,” and “Type 2 Diabetes Mellitus” as well as the targets of SGLT2 inhibitors. After screening the common targets, we used Cytoscape 3.8.2 software to construct SGLT2 inhibitors' regulatory network and protein-protein interaction network. The clusterProfiler R package was used to perform gene ontology functional analysis and Kyoto encyclopedia of genes and genomes pathway enrichment analyses on the target genes. Molecular docking was utilized to verify the relationship between SGLT2 inhibitors and core targets. Results Seven different SGLT2 inhibitors were found to have cardiorenal protective effects on 146 targets. The main mechanisms of action may be associated with lipid and atherosclerosis, MAPK signaling pathway, Rap1 signaling pathway, endocrine resistance, fluid shear stress, atherosclerosis, TNF signaling pathway, relaxin signaling pathway, neurotrophin signaling pathway, and AGEs-RAGE signaling pathway in diabetic complications were related. Docking of SGLT2 inhibitors with key targets such as GAPDH, MAPK3, MMP9, MAPK1, and NRAS revealed that these compounds bind to proteins spontaneously. Conclusion Based on pharmacological networks, this study elucidates the potential mechanisms of action of SGLT2 inhibitors from a systemic and holistic perspective. These key targets and pathways will provide new ideas for future studies on the pharmacological mechanisms of cardiorenal protection by SGLT2 inhibitors.
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Affiliation(s)
- Anzhu Wang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Graduate School, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zhendong Li
- Qingdao West Coast New Area People's Hospital, Qingdao, China
| | - Sun Zhuo
- Qingdao West Coast New Area People's Hospital, Qingdao, China
| | - Feng Gao
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Graduate School, China Academy of Chinese Medical Sciences, Beijing, China
| | - Hongwei Zhang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Graduate School, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zhibo Zhang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Beijing University of Chinese Medicine, Beijing, China
| | - Gaocan Ren
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Graduate School, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiaochang Ma
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Clinical Research Center for Chinese Medicine Cardiology, Beijing, China
- *Correspondence: Xiaochang Ma
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Qian D, Tian J, Wang S, Shan X, Zhao P, Chen H, Xu M, Guo W, Zhang C, Lu R. Trans-cinnamaldehyde protects against phenylephrine-induced cardiomyocyte hypertrophy through the CaMKII/ERK pathway. BMC Complement Med Ther 2022; 22:115. [PMID: 35468773 PMCID: PMC9040265 DOI: 10.1186/s12906-022-03594-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 04/14/2022] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND Trans-cinnamaldehyde (TCA) is one of the main pharmaceutical ingredients of Cinnamomum cassia Presl, which has been shown to have therapeutic effects on a variety of cardiovascular diseases. This study was carried out to characterize and reveal the underlying mechanisms of the protective effects of TCA against cardiac hypertrophy. METHODS We used phenylephrine (PE) to induce cardiac hypertrophy and treated with TCA in vivo and in vitro. In neonatal rat cardiomyocytes (NRCMs), RNA sequencing and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were carried out to identify potential pathways of TCA. Then, the phosphorylation and nuclear localization of calcium/calmodulin-dependent protein kinase II (CaMKII) and extracellular signal-related kinase (ERK) were detected. In adult mouse cardiomyocytes (AMCMs), calcium transients, calcium sparks, sarcomere shortening and the phosphorylation of several key proteins for calcium handling were evaluated. For mouse in vivo experiments, cardiac hypertrophy was evaluated by assessing morphological changes, echocardiographic parameters, and the expression of hypertrophic genes and proteins. RESULTS TCA suppressed PE-induced cardiac hypertrophy and the phosphorylation and nuclear localization of CaMKII and ERK in NRCMs. Our data also demonstrate that TCA blocked the hyperphosphorylation of ryanodine receptor type 2 (RyR2) and phospholamban (PLN) and restored Ca2+ handling and sarcomere shortening in AMCMs. Moreover, our data revealed that TCA alleviated PE-induced cardiac hypertrophy in adult mice and downregulated the phosphorylation of CaMKII and ERK. CONCLUSION TCA has a protective effect against PE-induced cardiac hypertrophy that may be associated with the inhibition of the CaMKII/ERK pathway.
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Affiliation(s)
- Dongdong Qian
- School of Basic Medical Science, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Jing Tian
- School of Basic Medical Science, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Department of Endocrinology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Sining Wang
- Department of Comprehensive Internal Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, 310012, China
| | - Xiaoli Shan
- Public Experiment Platform, School of Basic Medical Science, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Pei Zhao
- Public Experiment Platform, School of Basic Medical Science, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Huihua Chen
- School of Basic Medical Science, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Ming Xu
- Department of Physiology, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Wei Guo
- Department of Pathology, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Chen Zhang
- Department of Pathology, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Rong Lu
- School of Basic Medical Science, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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Harnessing RKIP to Combat Heart Disease and Cancer. Cancers (Basel) 2022; 14:cancers14040867. [PMID: 35205615 PMCID: PMC8870036 DOI: 10.3390/cancers14040867] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 02/01/2022] [Accepted: 02/07/2022] [Indexed: 02/06/2023] Open
Abstract
Cancer and heart disease are leading causes of morbidity and mortality worldwide. These diseases have common risk factors, common molecular signaling pathways that are central to their pathogenesis, and even some disease phenotypes that are interdependent. Thus, a detailed understanding of common regulators is critical for the development of new and synergistic therapeutic strategies. The Raf kinase inhibitory protein (RKIP) is a regulator of the cellular kinome that functions to maintain cellular robustness and prevent the progression of diseases including heart disease and cancer. Two of the key signaling pathways controlled by RKIP are the β-adrenergic receptor (βAR) signaling to protein kinase A (PKA), particularly in the heart, and the MAP kinase cascade Raf/MEK/ERK1/2 that regulates multiple diseases. The goal of this review is to discuss how we can leverage RKIP to suppress cancer without incurring deleterious effects on the heart. Specifically, we discuss: (1) How RKIP functions to either suppress or activate βAR (PKA) and ERK1/2 signaling; (2) How we can prevent cancer-promoting kinase signaling while at the same time avoiding cardiotoxicity.
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22
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Effect of Ghrelin Intervention on the Ras/ERK Pathway in the Regulation of Heart Failure by PTEN. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:1045681. [PMID: 35082908 PMCID: PMC8786517 DOI: 10.1155/2022/1045681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 11/27/2021] [Indexed: 11/17/2022]
Abstract
Objective. To study the possible mechanism of ghrelin in heart failure and how it works. Method. In vitro results demonstrated that ghrelin alleviates cardiac function and reduces myocardial fibrosis in rats with heart failure. Moreover, ghrelin intervention increased PTEN expression level and reduced ERK, c-jun, and c-Fos expression level; in vivo experiments demonstrated that ghrelin intervention reduces mast memory expression and increases cardiomyocyte surface area, PTEN expression level, ERK, c-jun, c-Fos expression level, and cell surface area, while ERK blockade suppresses mast gene expression and reduces cell surface area. Results. In vitro experimental results prove that we have successfully constructed a rat model related to heart failure, and ghrelin can alleviate the heart function of heart failure rats and reduce myocardial fibrosis. In addition, ghrelin is closely related to the decrease of the expression levels of ERK, c-jun, and c-Fos, but it can also increase the expression of PTEN in the rat model; in vivo experiments proved that we successfully constructed an in vitro cardiac hypertrophy model, and the intervention of ghrelin would reduce the expression of hypertrophic memory and increase the surface area of cardiomyocytes, increase the expression level of PTEN, and reduce the expression levels of ERK, c-jun, and c-Fos, while the blockade of PTEN will increase the expression of hypertrophy genes and increase the cell surface area, while the blockade of ERK will increase the expression of hypertrophic genes, which in turn will make the cell surface area reducing. Conclusion. Ghrelin inhibits the phosphorylation and nuclear entry of ERK by activating PTEN, thereby controlling the transcription of hypertrophic genes, improving myocardial hypertrophy, and enhancing cardiac function.
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