Hypertrophic cardiomyopathy is characterized by alterations of the mitochondrial calcium uniporter complex proteins: insights from patients with aortic valve stenosis versus hypertrophic obstructive cardiomyopathy
Introduction: Hypertrophies of the cardiac septum are caused either by aortic valve stenosis (AVS) or by congenital hypertrophic obstructive cardiomyopathy (HOCM). As they induce cardiac remodeling, these cardiac pathologies may promote an arrhythmogenic substrate with associated malignant ventricul...
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Frontiers Media S.A.
2023-11-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1264216/full |
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| author | Vera Paar Michael Haslinger Philipp Krombholz-Reindl Stefan Pittner Matthias Neuner Peter Jirak Peter Jirak Tobias Kolbitsch Bernd Minnich Falk Schrödl Alexandra Kaser-Eichberger Kristen Kopp Andreas Koller Clemens Steinwender Michael Lichtenauer Fabio C. Monticelli Rainald Seitelberger Uta C. Hoppe Christian Dinges Lukas J. Motloch Lukas J. Motloch Lukas J. Motloch |
| author_facet | Vera Paar Michael Haslinger Philipp Krombholz-Reindl Stefan Pittner Matthias Neuner Peter Jirak Peter Jirak Tobias Kolbitsch Bernd Minnich Falk Schrödl Alexandra Kaser-Eichberger Kristen Kopp Andreas Koller Clemens Steinwender Michael Lichtenauer Fabio C. Monticelli Rainald Seitelberger Uta C. Hoppe Christian Dinges Lukas J. Motloch Lukas J. Motloch Lukas J. Motloch |
| author_sort | Vera Paar |
| collection | DOAJ |
| description | Introduction: Hypertrophies of the cardiac septum are caused either by aortic valve stenosis (AVS) or by congenital hypertrophic obstructive cardiomyopathy (HOCM). As they induce cardiac remodeling, these cardiac pathologies may promote an arrhythmogenic substrate with associated malignant ventricular arrhythmias and may lead to heart failure. While altered calcium (Ca2+) handling seems to be a key player in the pathogenesis, the role of mitochondrial calcium handling was not investigated in these patients to date.Methods: To investigate this issue, cardiac septal samples were collected from patients undergoing myectomy during cardiac surgery for excessive septal hypertrophy and/or aortic valve replacement, caused by AVS and HOCM. Septal specimens were matched with cardiac tissue obtained from post-mortem controls without cardiac diseases (Ctrl).Results and discussion: Patient characteristics and most of the echocardiographic parameters did not differ between AVS and HOCM. Most notably, the interventricular septum thickness, diastolic (IVSd), was the greatest in HOCM patients. Histological and molecular analyses showed a trend towards higher fibrotic burden in both pathologies, when compared to Ctrl. Most notably, the mitochondrial Ca2+ uniporter (MCU) complex associated proteins were altered in both pathologies of left ventricular hypertrophy (LVH). On the one hand, the expression pattern of the MCU complex subunits MCU and MICU1 were shown to be markedly increased, especially in AVS. On the other hand, PRMT-1, UCP-2, and UCP-3 declined with hypertrophy. These conditions were associated with an increase in the expression patterns of the Ca2+ uptaking ion channel SERCA2a in AVS (p = 0.0013), though not in HOCM, compared to healthy tissue. Our data obtained from human specimen from AVS or HOCM indicates major alterations in the expression of the mitochondrial calcium uniporter complex and associated proteins. Thus, in cardiac septal hypertrophies, besides modifications of cytosolic calcium handling, impaired mitochondrial uptake might be a key player in disease progression. |
| first_indexed | 2024-03-10T00:09:13Z |
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| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-03-10T00:09:13Z |
| publishDate | 2023-11-01 |
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| series | Frontiers in Pharmacology |
| spelling | doaj.art-78c32d47ee014a5495a47d06850ea9cb2023-11-23T16:02:40ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-11-011410.3389/fphar.2023.12642161264216Hypertrophic cardiomyopathy is characterized by alterations of the mitochondrial calcium uniporter complex proteins: insights from patients with aortic valve stenosis versus hypertrophic obstructive cardiomyopathyVera Paar0Michael Haslinger1Philipp Krombholz-Reindl2Stefan Pittner3Matthias Neuner4Peter Jirak5Peter Jirak6Tobias Kolbitsch7Bernd Minnich8Falk Schrödl9Alexandra Kaser-Eichberger10Kristen Kopp11Andreas Koller12Clemens Steinwender13Michael Lichtenauer14Fabio C. Monticelli15Rainald Seitelberger16Uta C. Hoppe17Christian Dinges18Lukas J. Motloch19Lukas J. Motloch20Lukas J. Motloch21Department of Internal Medicine II, Paracelsus Medical University, Salzburg, AustriaDepartment of Internal Medicine II, Paracelsus Medical University, Salzburg, AustriaDepartment of Cardiac Surgery, Paracelsus Medical University, Salzburg, AustriaDepartment of Legal Medicine and Forensic Psychiatry, Paris-Lodron University of Salzburg, Salzburg, AustriaDepartment of Anesthesiology, Perioperative Medicine and Intensive Care Medicine, Paracelsus Medical University, Salzburg, AustriaDepartment of Internal Medicine II, Paracelsus Medical University, Salzburg, AustriaDepartment of Internal Medicine, Hospital Gmünd, Lower Austria, AustriaDepartment of Internal Medicine II, Paracelsus Medical University, Salzburg, AustriaDepartment of Environment and Biodiversity, Paris-Lodron University of Salzburg, Salzburg, AustriaCenter for Anatomy and Cell Biology, Institute of Anatomy and Cell Biology Salzburg, Paracelsus Medical University, Salzburg, AustriaCenter for Anatomy and Cell Biology, Institute of Anatomy and Cell Biology Salzburg, Paracelsus Medical University, Salzburg, AustriaDepartment of Internal Medicine II, Paracelsus Medical University, Salzburg, AustriaResearch Program for Experimental Ophthalmology and Glaucoma Research, Department of Ophthalmology and Optometry, Paracelsus Medical University, Salzburg, AustriaDepartment of Cardiology, Kepler University Hospital, Medical Faculty, Johannes Kepler University Linz, Linz, AustriaDepartment of Internal Medicine II, Paracelsus Medical University, Salzburg, AustriaDepartment of Legal Medicine and Forensic Psychiatry, Paris-Lodron University of Salzburg, Salzburg, AustriaDepartment of Cardiac Surgery, Paracelsus Medical University, Salzburg, AustriaDepartment of Internal Medicine II, Paracelsus Medical University, Salzburg, AustriaDepartment of Cardiac Surgery, Paracelsus Medical University, Salzburg, AustriaDepartment of Internal Medicine II, Paracelsus Medical University, Salzburg, AustriaDepartment of Cardiology, Kepler University Hospital, Medical Faculty, Johannes Kepler University Linz, Linz, Austria0Department of Internal Medicine II, Salzkammergut Klinikum, OÖG, Vöcklabruck, AustriaIntroduction: Hypertrophies of the cardiac septum are caused either by aortic valve stenosis (AVS) or by congenital hypertrophic obstructive cardiomyopathy (HOCM). As they induce cardiac remodeling, these cardiac pathologies may promote an arrhythmogenic substrate with associated malignant ventricular arrhythmias and may lead to heart failure. While altered calcium (Ca2+) handling seems to be a key player in the pathogenesis, the role of mitochondrial calcium handling was not investigated in these patients to date.Methods: To investigate this issue, cardiac septal samples were collected from patients undergoing myectomy during cardiac surgery for excessive septal hypertrophy and/or aortic valve replacement, caused by AVS and HOCM. Septal specimens were matched with cardiac tissue obtained from post-mortem controls without cardiac diseases (Ctrl).Results and discussion: Patient characteristics and most of the echocardiographic parameters did not differ between AVS and HOCM. Most notably, the interventricular septum thickness, diastolic (IVSd), was the greatest in HOCM patients. Histological and molecular analyses showed a trend towards higher fibrotic burden in both pathologies, when compared to Ctrl. Most notably, the mitochondrial Ca2+ uniporter (MCU) complex associated proteins were altered in both pathologies of left ventricular hypertrophy (LVH). On the one hand, the expression pattern of the MCU complex subunits MCU and MICU1 were shown to be markedly increased, especially in AVS. On the other hand, PRMT-1, UCP-2, and UCP-3 declined with hypertrophy. These conditions were associated with an increase in the expression patterns of the Ca2+ uptaking ion channel SERCA2a in AVS (p = 0.0013), though not in HOCM, compared to healthy tissue. Our data obtained from human specimen from AVS or HOCM indicates major alterations in the expression of the mitochondrial calcium uniporter complex and associated proteins. Thus, in cardiac septal hypertrophies, besides modifications of cytosolic calcium handling, impaired mitochondrial uptake might be a key player in disease progression.https://www.frontiersin.org/articles/10.3389/fphar.2023.1264216/fullleft ventricular hypertrophyaortic valve stenosishypertrophic obstructive cardiomyopathyfibrosiscalciummitochondria |
| spellingShingle | Vera Paar Michael Haslinger Philipp Krombholz-Reindl Stefan Pittner Matthias Neuner Peter Jirak Peter Jirak Tobias Kolbitsch Bernd Minnich Falk Schrödl Alexandra Kaser-Eichberger Kristen Kopp Andreas Koller Clemens Steinwender Michael Lichtenauer Fabio C. Monticelli Rainald Seitelberger Uta C. Hoppe Christian Dinges Lukas J. Motloch Lukas J. Motloch Lukas J. Motloch Hypertrophic cardiomyopathy is characterized by alterations of the mitochondrial calcium uniporter complex proteins: insights from patients with aortic valve stenosis versus hypertrophic obstructive cardiomyopathy Frontiers in Pharmacology left ventricular hypertrophy aortic valve stenosis hypertrophic obstructive cardiomyopathy fibrosis calcium mitochondria |
| title | Hypertrophic cardiomyopathy is characterized by alterations of the mitochondrial calcium uniporter complex proteins: insights from patients with aortic valve stenosis versus hypertrophic obstructive cardiomyopathy |
| title_full | Hypertrophic cardiomyopathy is characterized by alterations of the mitochondrial calcium uniporter complex proteins: insights from patients with aortic valve stenosis versus hypertrophic obstructive cardiomyopathy |
| title_fullStr | Hypertrophic cardiomyopathy is characterized by alterations of the mitochondrial calcium uniporter complex proteins: insights from patients with aortic valve stenosis versus hypertrophic obstructive cardiomyopathy |
| title_full_unstemmed | Hypertrophic cardiomyopathy is characterized by alterations of the mitochondrial calcium uniporter complex proteins: insights from patients with aortic valve stenosis versus hypertrophic obstructive cardiomyopathy |
| title_short | Hypertrophic cardiomyopathy is characterized by alterations of the mitochondrial calcium uniporter complex proteins: insights from patients with aortic valve stenosis versus hypertrophic obstructive cardiomyopathy |
| title_sort | hypertrophic cardiomyopathy is characterized by alterations of the mitochondrial calcium uniporter complex proteins insights from patients with aortic valve stenosis versus hypertrophic obstructive cardiomyopathy |
| topic | left ventricular hypertrophy aortic valve stenosis hypertrophic obstructive cardiomyopathy fibrosis calcium mitochondria |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1264216/full |
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