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Cardiomyocytes, Myocardial Hypertrophy, and Heart Failure
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Cardiomyocytes, Myocardial Hypertrophy, and Heart Failure

A topical collection in Cells (ISSN 2073-4409). This collection belongs to the section "Cellular Pathology".

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Editor

Prof. Dr. Klaus-Dieter Schlüter

E-Mail Website
Collection Editor
Institute of Physiology, Justus-Liebig-Universität Giessen, Aulweg 129, 35392 Giessen, Germany
Interests: cardiac hypertrophy; heart failure; cardiomyocytes; metabolism; hypertension
Special Issues, Collections and Topics in MDPI journals

Topical Collection Information

Dear Colleagues,

Heart failure is still a leading cause of mortality worldwide. It is caused by cardiomyocytes that lose the ability to generate sufficient force to pump blood into circulation. To improve the current treatment options in cardiology, it is important to have a better understanding of the biological behavior of cardiomyocytes. The function of these cells cannot be completely understood independently of the interaction with surrounding cells, i.e., cardiac fibroblasts and vascular cells. Nevertheless, cardiomyocytes are the cells that have to improve heart work. It is becoming evident that the transition from hypertrophy, an adaptive mechanism to compensate for increased power requirements, to heart failure is the key step to understand how heart function is becoming insufficient. Processes dealing with metabolism, electromechanical coupling, and electrophysiological aspects are among those processes that need to be addressed and understood in their molecular fine regulation in order to improve treatment regimes.

This Topical Collection aims to summarize the current understanding of the process of developing heart failure with a focus on the force-generating cell, the cardiomyocyte.

We look forward to your contributions.

Prof. Dr. Klaus-Dieter Schlüter
Collection Editor

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Keywords

  • Cardiac metabolism
  • Electromechanical coupling
  • Regulation of growth and cell death in the heart
  • Right heart failure
  • Electrophysiological aspects of cardiomyocytes

Published Papers (8 papers)

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2022

Jump to: 2021

24 pages, 3319 KiB  
Article
PGC-1α4 Interacts with REST to Upregulate Neuronal Genes and Augment Energy Consumption in Developing Cardiomyocytes
by Tomi Tuomainen, Nikolay Naumenko, Maija Mutikainen, Anastasia Shakirzyanova, Sarah Sczelecki, Jennifer L. Estall, Jorge L. Ruas and Pasi Tavi
Cells 2022, 11(19), 2944; https://doi.org/10.3390/cells11192944 - 20 Sep 2022
Cited by 2 | Viewed by 1764
Abstract
Transcriptional coactivator PGC-1α is a main regulator of cardiac energy metabolism. In addition to canonical PGC-1α1, other PGC-1α isoforms have been found to exert specific biological functions in a variety of tissues. We investigated the expression patterns and the biological effects of the [...] Read more.
Transcriptional coactivator PGC-1α is a main regulator of cardiac energy metabolism. In addition to canonical PGC-1α1, other PGC-1α isoforms have been found to exert specific biological functions in a variety of tissues. We investigated the expression patterns and the biological effects of the non-canonical isoforms in the heart. We used RNA sequencing data to identify the expression patterns of PGC-1α isoforms in the heart. To evaluate the biological effects of the alternative isoform expression, we generated a transgenic mouse with cardiac-specific overexpression of PGC-1α4 and analysed the cardiac phenotype with a wide spectrum of physiological and biophysical tools. Our results show that non-canonical isoforms are expressed in the heart, and that the main variant PGC-1α4 is induced by β-adrenergic signalling in adult cardiomyocytes. Cardiomyocyte specific PGC-1α4 overexpression in mice relieves the RE1-Silencing Transcription factor (REST)-mediated suppression of neuronal genes during foetal heart development. The resulting de-repression of REST target genes induces a cardiac phenotype with increased cellular energy consumption, resulting in postnatal dilated cardiomyopathy. These results propose a new concept for actions of the PGC-1α protein family where activation of the Pgc-1α gene, through its isoforms, induces a phenotype with concurrent supply and demand for cellular energy. These data highlight the biological roles of the different PGC-1α isoforms, which should be considered when future therapies are developed. Full article
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18 pages, 6653 KiB  
Review
The Cardiomyocyte in Heart Failure with Preserved Ejection Fraction—Victim of Its Environment?
by Angela Rocca, Ruud B. van Heeswijk, Jonas Richiardi, Philippe Meyer and Roger Hullin
Cells 2022, 11(5), 867; https://doi.org/10.3390/cells11050867 - 02 Mar 2022
Cited by 2 | Viewed by 3160
Abstract
Heart failure (HF) with preserved left ventricular ejection fraction (HFpEF) is becoming the predominant form of HF. However, medical therapy that improves cardiovascular outcome in HF patients with almost normal and normal systolic left ventricular function, but diastolic dysfunction is missing. The cause [...] Read more.
Heart failure (HF) with preserved left ventricular ejection fraction (HFpEF) is becoming the predominant form of HF. However, medical therapy that improves cardiovascular outcome in HF patients with almost normal and normal systolic left ventricular function, but diastolic dysfunction is missing. The cause of this unmet need is incomplete understanding of HFpEF pathophysiology, the heterogeneity of the patient population, and poor matching of therapeutic mechanisms and primary pathophysiological processes. Recently, animal models improved understanding of the pathophysiological role of highly prevalent and often concomitantly presenting comorbidity in HFpEF patients. Evidence from these animal models provide first insight into cellular pathophysiology not considered so far in HFpEF disease, promising that improved understanding may provide new therapeutical targets. This review merges observation from animal models and human HFpEF disease with the intention to converge cardiomyocytes pathophysiological aspects and clinical knowledge. Full article
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18 pages, 2761 KiB  
Article
The Effects of Mechanical Loading Variations on the Hypertrophic, Anti-Apoptotic, and Anti-Inflammatory Responses of Differentiated Cardiomyocyte-like H9C2 Cells
by Evangelos Zevolis, Anastassios Philippou, Athanasios Moustogiannis, Antonios Chatzigeorgiou and Michael Koutsilieris
Cells 2022, 11(3), 473; https://doi.org/10.3390/cells11030473 - 29 Jan 2022
Cited by 3 | Viewed by 3150
Abstract
Cardiomyocytes possess the ability to respond to mechanical stimuli by adapting their biological functions. This study investigated cellular and molecular events in cardiomyocyte-like H9C2 cells during differentiation as well as the signalling and gene expression responses of the differentiated cells under various mechanical [...] Read more.
Cardiomyocytes possess the ability to respond to mechanical stimuli by adapting their biological functions. This study investigated cellular and molecular events in cardiomyocyte-like H9C2 cells during differentiation as well as the signalling and gene expression responses of the differentiated cells under various mechanical stretching protocols in vitro. Immunofluorescence was used to monitor MyHC expression and structural changes during cardiomyoblast differentiation. Moreover, alterations in the expression of cardiac-specific markers, cell cycle regulatory factors, MRFs, hypertrophic, apoptotic, atrophy and inflammatory factors, as well as the activation of major intracellular signalling pathways were evaluated during differentiation and under mechanical stretching of the differentiated H9C2 cells. Compared to undifferentiated cells, advanced-differentiation cardiomyoblasts exhibited increased expression of cardiac-specific markers, MyHC, MRFs, and IGF-1 isoforms. Moreover, differentiated cells that underwent a low strain/frequency mechanical loading protocol of intermediate duration showed enhanced expression of MRFs and hypertrophic factors, along with a decreased expression of apoptotic, atrophy, and inflammatory factors compared to both high-strain/frequency loading protocols and to unloaded cells. These findings suggest that altering the strain and frequency of mechanical loading applied on differentiated H9C2 cardiomyoblasts can regulate their anabolic/survival program, with a low-strain/frequency stretching being, overall, most effective at inducing beneficial responses. Full article
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2021

Jump to: 2022

24 pages, 8874 KiB  
Article
Autophagy and Endoplasmic Reticulum Stress during Onset and Progression of Arrhythmogenic Cardiomyopathy
by Mark Pitsch, Sebastian Kant, Corinna Mytzka, Rudolf E. Leube and Claudia A. Krusche
Cells 2022, 11(1), 96; https://doi.org/10.3390/cells11010096 - 29 Dec 2021
Cited by 6 | Viewed by 2468
Abstract
Arrhythmogenic cardiomyopathy (AC) is a heritable, potentially lethal disease without a causal therapy. AC is characterized by focal cardiomyocyte death followed by inflammation and progressive formation of connective tissue. The pathomechanisms leading to structural disease onset and progression, however, are not fully elucidated. [...] Read more.
Arrhythmogenic cardiomyopathy (AC) is a heritable, potentially lethal disease without a causal therapy. AC is characterized by focal cardiomyocyte death followed by inflammation and progressive formation of connective tissue. The pathomechanisms leading to structural disease onset and progression, however, are not fully elucidated. Recent studies revealed that dysregulation of autophagy and endoplasmic/sarcoplasmic reticulum (ER/SR) stress plays an important role in cardiac pathophysiology. We therefore examined the temporal and spatial expression patterns of autophagy and ER/SR stress indicators in murine AC models by qRT-PCR, immunohistochemistry, in situ hybridization and electron microscopy. Cardiomyocytes overexpressing the autophagy markers LC3 and SQSTM1/p62 and containing prominent autophagic vacuoles were detected next to regions of inflammation and fibrosis during onset and chronic disease progression. mRNAs of the ER stress markers Chop and sXbp1 were elevated in both ventricles at disease onset. During chronic disease progression Chop mRNA was upregulated in right ventricles. In addition, reduced Ryr2 mRNA expression together with often drastically enlarged ER/SR cisternae further indicated SR dysfunction during this disease phase. Our observations support the hypothesis that locally altered autophagy and enhanced ER/SR stress play a role in AC pathogenesis both at the onset and during chronic progression. Full article
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16 pages, 3152 KiB  
Article
HOPX Plays a Critical Role in Antiretroviral Drugs Induced Epigenetic Modification and Cardiac Hypertrophy
by Shiridhar Kashyap, Maryam Rabbani, Isabela de Lima, Olena Kondrachuk, Raj Patel, Mahnoush Sophia Shafiei, Avni Mukker, Aishwarya Rajakumar and Manish Kumar Gupta
Cells 2021, 10(12), 3458; https://doi.org/10.3390/cells10123458 - 08 Dec 2021
Cited by 2 | Viewed by 3045
Abstract
People living with HIV (PLWH) have to take an antiretroviral therapy (ART) for life and show noncommunicable illnesses such as chronic inflammation, immune activation, and multiorgan dysregulation. Recent studies suggest that long-term use of ART induces comorbid conditions and is one of the [...] Read more.
People living with HIV (PLWH) have to take an antiretroviral therapy (ART) for life and show noncommunicable illnesses such as chronic inflammation, immune activation, and multiorgan dysregulation. Recent studies suggest that long-term use of ART induces comorbid conditions and is one of the leading causes of heart failure in PLWH. However, the molecular mechanism of antiretroviral drugs (ARVs) induced heart failure is unclear. To determine the mechanism of ARVs induced cardiac dysfunction, we performed global transcriptomic profiling of ARVs treated neonatal rat ventricular cardiomyocytes in culture. Differentially expressed genes were identified by RNA-sequencing. Our data show that ARVs treatment causes upregulation of several biological functions associated with cardiotoxicity, hypertrophy, and heart failure. Global gene expression data were validated in cardiac tissue isolated from HIV patients having a history of ART. Interestingly, we found that homeodomain-only protein homeobox (HOPX) expression was significantly increased in cardiomyocytes treated with ARVs and in the heart tissue of HIV patients. Furthermore, we found that HOPX plays a crucial role in ARVs mediated cellular hypertrophy. Mechanistically, we found that HOPX plays a critical role in epigenetic regulation, through deacetylation of histone, while the HDAC inhibitor, Trichostatin A, can restore the acetylation level of histone 3 in the presence of ARVs. Full article
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16 pages, 4291 KiB  
Article
Modeling Hypoxic Stress In Vitro Using Human Embryonic Stem Cells Derived Cardiomyocytes Matured by FGF4 and Ascorbic Acid Treatment
by Seung-Cheol Choi, Ha-Rim Seo, Long-Hui Cui, Myeong-Hwa Song, Ji-Min Noh, Kyung-Seob Kim, Ji-Hyun Choi, Jong-Ho Kim, Chi-Yeon Park, Hyung Joon Joo, Soon Jun Hong, Tae Hee Ko, Jong-Il Choi, Hyo Jin Kim, Jong-Hoon Kim, Se-Hwan Paek, Ji-Na Park, Dong-Hyung Kim, Yongjun Jang, Yongdoo Park and Do-Sun Limadd Show full author list remove Hide full author list
Cells 2021, 10(10), 2741; https://doi.org/10.3390/cells10102741 - 14 Oct 2021
Cited by 4 | Viewed by 2437
Abstract
Mature cardiomyocytes (CMs) obtained from human pluripotent stem cells (hPSCs) have been required for more accurate in vitro modeling of adult-onset cardiac disease and drug discovery. Here, we found that FGF4 and ascorbic acid (AA) induce differentiation of BG01 human embryonic stem cell–cardiogenic [...] Read more.
Mature cardiomyocytes (CMs) obtained from human pluripotent stem cells (hPSCs) have been required for more accurate in vitro modeling of adult-onset cardiac disease and drug discovery. Here, we found that FGF4 and ascorbic acid (AA) induce differentiation of BG01 human embryonic stem cell–cardiogenic mesoderm cells (hESC-CMCs) into mature and ventricular CMs. Co-treatment of BG01 hESC-CMCs with FGF4+AA synergistically induced differentiation into mature and ventricular CMs. FGF4+AA-treated BG01 hESC-CMs robustly released acute myocardial infarction (AMI) biomarkers (cTnI, CK-MB, and myoglobin) into culture medium in response to hypoxic injury. Hypoxia-responsive genes and potential cardiac biomarkers proved in the diagnosis and prognosis of coronary artery diseases were induced in FGF4+AA-treated BG01 hESC-CMs in response to hypoxia based on transcriptome analyses. This study demonstrates that it is feasible to model hypoxic stress in vitro using hESC-CMs matured by soluble factors. Full article
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19 pages, 5329 KiB  
Article
BMP-7 Attenuates Inflammation-Induced Pyroptosis and Improves Cardiac Repair in Diabetic Cardiomyopathy
by Ibrahim Elmadbouh and Dinender K. Singla
Cells 2021, 10(10), 2640; https://doi.org/10.3390/cells10102640 - 02 Oct 2021
Cited by 35 | Viewed by 5486
Abstract
In the present study, we investigated a novel signaling target in diabetic cardiomyopathy where inflammation induces caspase-1-dependent cell death, pyroptosis, involving Nek7-GBP5 activators to activate the NLRP3 inflammasome, destabilizes cardiac structure and neovascularization. Furthermore, we explored the therapeutic ability of bone morphogenetic protein-7 [...] Read more.
In the present study, we investigated a novel signaling target in diabetic cardiomyopathy where inflammation induces caspase-1-dependent cell death, pyroptosis, involving Nek7-GBP5 activators to activate the NLRP3 inflammasome, destabilizes cardiac structure and neovascularization. Furthermore, we explored the therapeutic ability of bone morphogenetic protein-7 (BMP-7) to attenuate these adverse effects. C57BL/6J mice (n = 16 mice/group) were divided into: control (200 mg/kg, 0.9% saline intraperitoneal injection, i.p.); Streptozotocin (STZ) and STZ-BMP-7 groups (STZ, 200 mg/kg, i.p. injection). After 6 weeks, heart function was examined with echocardiography, and mice were sacrificed. Immunostaining, Western blotting, H&E, and Masson’s trichrome staining was performed on heart tissues. STZ-induced diabetic cardiomyopathy significantly increased inflammasome formation (TLR4, NLRP3, Nek7, and GBP5), pyroptosis markers (caspase-1, IL-1β, and IL-18), inflammatory cytokines (IL-6 and TNF-α), MMP9, and infiltration of monocytes (CD14), macrophage (iNOS), and dendritic cells (CD11b and CD11c) (p < 0.05). Moreover, a significant endothelial progenitor cells (EPCs) dysfunction (c-Kit/FLk-1, CD31), adverse cardiac remodeling, and reduction in left ventricular (LV) heart function were observed in STZ versus control (p < 0.05). Treatment with BMP-7 significantly reduced inflammasome formation, pyroptosis, and inflammatory cytokines and infiltrated inflammatory cells. In addition, BMP-7 treatment enhanced EPC markers and neovascularization and subsequently improved cardiac remodeling in a diabetic heart. Moreover, a significant improvement in LV heart function was achieved after BMP-7 administration relative to diabetic mice (p < 0.05). In conclusion, BMP-7 attenuated inflammation-induced pyroptosis, adverse cardiac remodeling, and improved heart function via the TLR4-NLRP3 inflammasome complex activated by novel signaling Nek7/GBP5. Our BMP-7 pre-clinical studies of mice could have significant potential as a future therapy for diabetic patients. Full article
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12 pages, 1458 KiB  
Article
Exercise Training Enhances Angiogenesis-Related Gene Responses in Skeletal Muscle of Patients with Chronic Heart Failure
by Andrea Tryfonos, Giorgos Tzanis, Theodore Pitsolis, Eleftherios Karatzanos, Michael Koutsilieris, Serafim Nanas and Anastassios Philippou
Cells 2021, 10(8), 1915; https://doi.org/10.3390/cells10081915 - 28 Jul 2021
Cited by 14 | Viewed by 2739
Abstract
Peripheral myopathy consists of a hallmark of heart failure (HF). Exercise enhanced skeletal muscle angiogenesis, and thus, it can be further beneficial towards the HF-induced myopathy. However, there is limited evidence regarding the exercise type that elicits optimum angiogenic responses of skeletal muscle [...] Read more.
Peripheral myopathy consists of a hallmark of heart failure (HF). Exercise enhanced skeletal muscle angiogenesis, and thus, it can be further beneficial towards the HF-induced myopathy. However, there is limited evidence regarding the exercise type that elicits optimum angiogenic responses of skeletal muscle in HF patients. This study aimed to (a) compare the effects of a high-intensity-interval-training (HIIT) or combined HIIT with strength training (COM) exercise protocol on the expression of angiogenesis-related factors in skeletal muscle of HF patients, and (b) examine the potential associations between the expression of those genes and capillarization in the trained muscles. Thirteen male patients with chronic HF (age: 51 ± 13 y; BMI: 27 ± 4 kg/m2) were randomly assigned to a 3-month exercise program that consisted of either HIIT (N = 6) or COM training (N = 7). Vastus lateralis muscle biopsies were performed pre- and post-training. RT-PCR was used to quantify the fold changes in mRNA expression of vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor 2 (VEGFR-2), hypoxia-inducible factor 1 alpha (HIF-1α), angiopoietin 1 (Ang-1), angiopoietin 2 (Ang-2), angiopoietin receptor (Tie2), and matrix metallopeptidase 9 (MMP-9), and immunohistochemistry to assess capillarization in skeletal muscle post-training. There was an overall increase in the expression levels of VEGF, VEGFR-2, HIF-1α, Ang2, and MMP9 post-training, while these changes were not different among groups. Changes in capillary-to-fibre ratio were found to be strongly associated with Tie2 and HIF-1α expression. This was the first study demonstrating that both HIIT and combined HIIT with strength training enhanced similarly the expression profile of angiogenic factors in skeletal muscle of HF patients, possibly driving the angiogenic program in the trained muscles, although those gene expression increases were found to be only partially related with muscle capillarization. Full article
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