{"title":"Unravelling the metabolic rewiring in the context of doxorubicin-induced cardiotoxicity: Fuel preference changes from fatty acids to glucose oxidation","authors":"Giulia Guerra , Michele Russo , Rebecca Priolo , Chiara Riganti , Simone Reano , Nicoletta Filigheddu , Emilio Hirsch , Alessandra Ghigo","doi":"10.1016/j.vph.2024.107324","DOIUrl":"https://doi.org/10.1016/j.vph.2024.107324","url":null,"abstract":"<div><p>Doxorubicin (DOX) is a highly effective chemotherapeutic agent whose clinical use is hindered by the onset of cardiotoxic effects, resulting in reduced ejection fraction within the first year from treatment initiation. Recently it has been demonstrated that DOX accumulates within mitochondria, leading to disruption of metabolic processes and energetic imbalance. We previously described that phosphoinositide 3-kinase γ (PI3Kγ) contributes to DOX-induced cardiotoxicity, causing autophagy inhibition and accumulation of damaged mitochondria. Here we intend to describe the maladaptive metabolic rewiring occurring in DOX-treated hearts and the contribution of PI3Kγ signalling to this process.</p><p>Metabolomic analysis of DOX-treated WT hearts revealed an accumulation of TCA cycle metabolites due to a cycle slowdown, with reduced levels of pyruvate, unchanged abundance of lactate and increased Acetyl-CoA production. Moreover, the activity of glycolytic enzymes was upregulated, and fatty acid oxidation downregulated, after DOX, indicative of increased glucose oxidation. In agreement, oxygen consumption was increased in after pyruvate supplementation, with the formation of cytotoxic ROS rather than energy production. These metabolic changes were fully prevented in KD hearts. Interestingly, they failed to increase glucose oxidation in response to DOX even with autophagy inhibition, indicating that PI3Kγ likely controls the fuel preference after DOX through an autophagy-independent mechanism. In vitro experiments showed that inhibition of PI3Kγ inhibits pyruvate dehydrogenase (PDH), the key enzyme of Randle cycle regulating the switch from fatty acids to glucose usage, while decreasing DOX-induced mobilization of GLUT-4-carrying vesicles to the plasma membrane and limiting the ensuing glucose uptake.</p><p>These results demonstrate that PI3Kγ promotes a maladaptive metabolic rewiring in DOX-treated hearts, through a two-pronged mechanism controlling PDH activation and GLUT-4-mediated glucose uptake.</p></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"155 ","pages":"Article 107324"},"PeriodicalIF":4.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141423806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sogol Sedighi , Sai Phyo , Maria Grazia Perino , Matt Oberdier , Sara Fink , Silvia Cetrullo , Flavio Flamigni , Henry Halperin , Ben Prosser , Ed Lakatta , Giulio Agnetti
{"title":"Understanding the pathobiology of intermediate filaments to curb acute and chronic cardiac dysfunction","authors":"Sogol Sedighi , Sai Phyo , Maria Grazia Perino , Matt Oberdier , Sara Fink , Silvia Cetrullo , Flavio Flamigni , Henry Halperin , Ben Prosser , Ed Lakatta , Giulio Agnetti","doi":"10.1016/j.vph.2024.107290","DOIUrl":"https://doi.org/10.1016/j.vph.2024.107290","url":null,"abstract":"","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"155 ","pages":"Article 107290"},"PeriodicalIF":4.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141424563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Marycarmen Arévalo-Martinez , Jacob Ede , Oscar van der Have , Olivia Ritsvall , Fredrik R. Zetterberg , Ulf J. Nilsson , Hakon Leffler , Johan Holmberg , Sebastian Albinsson
{"title":"Myocardin related transcription factor and galectin-3 drive lipid accumulation in human blood vessels","authors":"Marycarmen Arévalo-Martinez , Jacob Ede , Oscar van der Have , Olivia Ritsvall , Fredrik R. Zetterberg , Ulf J. Nilsson , Hakon Leffler , Johan Holmberg , Sebastian Albinsson","doi":"10.1016/j.vph.2024.107383","DOIUrl":"10.1016/j.vph.2024.107383","url":null,"abstract":"<div><h3>Objective</h3><p>Diabetes and hypertension are important risk factors for vascular disease, including atherosclerosis. A driving factor in this process is lipid accumulation in smooth muscle cells of the vascular wall. The glucose- and mechano-sensitive transcriptional coactivator, myocardin-related transcription factor A (MRTF-A/MKL1) can promote lipid accumulation in cultured human smooth muscle cells and contribute to the formation of smooth muscle-derived foam cells. The purpose of this study was to determine if intact human blood vessels <em>ex vivo</em> can be used to evaluate lipid accumulation in the vascular wall, and if this process is dependent on MRTF and/or galectin-3/<em>LGALS3</em>. Galectin-3 is an early marker of smooth muscle transdifferentiation and a potential mediator for foam cell formation and atherosclerosis.</p></div><div><h3>Approach and results</h3><p>Human mammary arteries and saphenous veins were exposed to altered cholesterol and glucose levels in an organ culture model. Accumulation of lipids, quantified by Oil Red O, was increased by cholesterol loading and elevated glucose concentrations. Pharmacological inhibition of MRTF with CCG-203971 decreased lipid accumulation, whereas adenoviral-mediated overexpression of MRTF-A had the opposite effect. Cholesterol-induced expression of galectin-3 was decreased after inhibition of MRTF. Importantly, pharmacological inhibition of galectin-3 with GB1107 reduced lipid accumulation in the vascular wall after cholesterol loading.</p></div><div><h3>Conclusion</h3><p><em>Ex vivo</em> organ culture of human arteries and veins can be used to evaluate lipid accumulation in the intact vascular wall, as well as adenoviral transduction and pharmacological inhibition. Although MRTF and galectin-3 may have beneficial, anti-inflammatory effects under certain circumstances, our results, which demonstrate a significant decrease in lipid accumulation, support further evaluation of MRTF- and galectin-3-inhibitors for therapeutic intervention against atherosclerotic vascular disease.</p></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"156 ","pages":"Article 107383"},"PeriodicalIF":4.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141234706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Silvia Berrettoni , Michelle Mendiola Pla , Franklin H. Lee , Giacomo Rozzi , Ryan T. Gross , Amy Evans , David C. Wendell , Paul Lezberg , Margherita Burattini , Francesco Paolo lo Muzio , Lorenzo Fassina , Carmelo A. Milano , Marie-Louise Bang , Dawn E. Bowles , Michele Miragoli
{"title":"Video analysis of ex-vivo beating hearts during preservation on the TransMedics® organ care system","authors":"Silvia Berrettoni , Michelle Mendiola Pla , Franklin H. Lee , Giacomo Rozzi , Ryan T. Gross , Amy Evans , David C. Wendell , Paul Lezberg , Margherita Burattini , Francesco Paolo lo Muzio , Lorenzo Fassina , Carmelo A. Milano , Marie-Louise Bang , Dawn E. Bowles , Michele Miragoli","doi":"10.1016/j.vph.2024.107299","DOIUrl":"https://doi.org/10.1016/j.vph.2024.107299","url":null,"abstract":"","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"155 ","pages":"Article 107299"},"PeriodicalIF":4.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141422646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
David Molla , Anthony Frosio , Giorgia Bertoli , Chiara Piantoni , Martina Arici , Chiara Bartolucci , Procolo Marchese , Claudia Bazzini , Andrea Barbuti , Marcella Rocchetti , Stefano Severi , Annalisa Bucchi , Mirko Baruscotti
{"title":"In-vitro studies of the NaV1.5 S805L Brugada mutation: The resting cell voltage is a critical element in determining the pathological or physiological phenotype of the current","authors":"David Molla , Anthony Frosio , Giorgia Bertoli , Chiara Piantoni , Martina Arici , Chiara Bartolucci , Procolo Marchese , Claudia Bazzini , Andrea Barbuti , Marcella Rocchetti , Stefano Severi , Annalisa Bucchi , Mirko Baruscotti","doi":"10.1016/j.vph.2024.107337","DOIUrl":"https://doi.org/10.1016/j.vph.2024.107337","url":null,"abstract":"","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"155 ","pages":"Article 107337"},"PeriodicalIF":4.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141422733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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