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14 pages, 1259 KiB  
Review
Engineered Hydrogels for Musculoskeletal Regeneration: Advanced Synthesis Strategies and Therapeutic Efficacy in Preclinical Models
by Gabriela Calin, Mihnea Costescu, Marcela Nour (Cârlig), Tudor Ciuhodaru, Batîr-Marin Denisa, Letitia Doina Duceac, Cozmin Mihai, Melania Florina Munteanu, Svetlana Trifunschi, Alexandru Oancea and Daniela Liliana Damir
Polymers 2025, 17(15), 2094; https://doi.org/10.3390/polym17152094 - 30 Jul 2025
Abstract
According to the World Health Organization, musculoskeletal injuries affect more than 1.71 billion people around the world. These injuries are a major public health issue and the leading cause of disability. There has been a recent interest in hydrogels as a potential biomaterial [...] Read more.
According to the World Health Organization, musculoskeletal injuries affect more than 1.71 billion people around the world. These injuries are a major public health issue and the leading cause of disability. There has been a recent interest in hydrogels as a potential biomaterial for musculoskeletal tissue regeneration. This is due to their high water content (70–99%), ECM-like structure, injectability, and controllable degradation rates. Recent preclinical studies indicate that they can enhance regeneration by modulating the release of bioactive compounds, growth factors, and stem cells. Composite hydrogels that combine natural and synthetic polymers, like chitosan and collagen, have compressive moduli that are advantageous for tendon–bone healing. Some of these hydrogels can even hold up to 0.8 MPa of tensile strength. In osteoarthritis models, functionalized systems such as microspheres responsive to matrix metalloproteinase-13 have demonstrated disease modulation and targeted drug delivery, while intelligent in situ hydrogels have exhibited a 43% increase in neovascularization and a 50% enhancement in myotube production. Hydrogel-based therapies have been shown to restore contractile force by as much as 80%, increase myofiber density by 65%, and boost ALP activity in bone defects by 2.1 times in volumetric muscle loss (VML) models. Adding TGF-β3 or MSCs to hydrogel systems improved GAG content by about 60%, collagen II expression by 35–50%, and O’Driscoll scores by 35–50% in cartilage regeneration. Full article
(This article belongs to the Section Polymer Applications)
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25 pages, 6067 KiB  
Article
Early-Stage Alcoholic Cardiomyopathy Highlighted by Metabolic Remodeling, Oxidative Stress, and Cardiac Myosin Dysfunction in Male Rats
by David V. Rasicci, Jinghua Ge, Adrien P. Chen, Neil B. Wood, Skylar M. L. Bodt, Allyson L. Toro, Alexandra Evans, Omid Golestanian, Md Shahrier Amin, Anne Pruznak, Nelli Mnatsakanyan, Yuval Silberman, Michael D. Dennis, Michael J. Previs, Charles H. Lang and Christopher M. Yengo
Int. J. Mol. Sci. 2025, 26(14), 6766; https://doi.org/10.3390/ijms26146766 - 15 Jul 2025
Viewed by 238
Abstract
Chronic ethanol use can lead to alcoholic cardiomyopathy (ACM), while the impact on the molecular and cellular aspects of the myocardium is unclear. Accordingly, male Sprague-Dawley rats were exposed to an ethanol-containing diet for 16 weeks and compared with a control group that [...] Read more.
Chronic ethanol use can lead to alcoholic cardiomyopathy (ACM), while the impact on the molecular and cellular aspects of the myocardium is unclear. Accordingly, male Sprague-Dawley rats were exposed to an ethanol-containing diet for 16 weeks and compared with a control group that was fed an isocaloric diet. Histological measurements from H&E slides revealed no significant differences in cell size. A proteomic approach revealed that alcohol exposure leads to enhanced mitochondrial lipid metabolism, and electron microscopy revealed impairments in mitochondrial morphology/density. Cardiac myosin purified from the hearts of ethanol-exposed animals demonstrated a 15% reduction in high-salt ATPase activity, with no significant changes in the in vitro motility and low-salt ATPase or formation of the super-relaxed (SRX) state. A protein carbonyl assay indicated a 20% increase in carbonyl incorporation, suggesting that alcohol may impact cardiac myosin through oxidative stress mechanisms. In vitro oxidation of healthy cardiac myosin revealed a dramatic decline in ATPase activity and in vitro motility, demonstrating a link between myosin protein oxidation and myosin mechanochemistry. Collectively, this study suggests alcohol-induced metabolic remodeling may be the initial insult that eventually leads to defects in the contractile machinery in the myocardium of ACM hearts. Full article
(This article belongs to the Special Issue Sarcomeric Proteins in Health and Disease: 3rd Edition)
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22 pages, 1439 KiB  
Review
Involvement of Oxidative Stress in Mitochondrial Abnormalities During the Development of Heart Disease
by Naranjan S. Dhalla, Petr Ostadal and Paramjit S. Tappia
Biomedicines 2025, 13(6), 1338; https://doi.org/10.3390/biomedicines13061338 - 29 May 2025
Viewed by 846
Abstract
Background: Several mitochondrial abnormalities such as defective energy production, depletion of energy stores, Ca2+ accumulation, generation of reactive oxygen species, and impaired intracellular signaling are associated with cardiac dysfunction during the development of different heart diseases. Methods: A narrative review was compiled [...] Read more.
Background: Several mitochondrial abnormalities such as defective energy production, depletion of energy stores, Ca2+ accumulation, generation of reactive oxygen species, and impaired intracellular signaling are associated with cardiac dysfunction during the development of different heart diseases. Methods: A narrative review was compiled by a search for applicable literature in MEDLINE via PubMed. Results: Mitochondria generate ATP through the processes of electron transport and oxidative phosphorylation, which is used as energy for cardiac contractile function. Mitochondria, in fact, are the key subcellular organelle for the regulation of intracellular Ca2+ concentration and are considered to serve as a buffer to maintain Ca2+ homeostasis in cardiomyocytes. However, during the development of heart disease, the excessive accumulation of intracellular Ca2+ results in mitochondria Ca2+-overload, which, in turn, impairs mitochondrial energy production and induces cardiac dysfunction. Mitochondria also generate reactive oxygen species (ROS), including superoxide anion radicals and hydroxyl radicals as well as non-radical oxidants such as hydrogen peroxide, which promote lipid peroxidation and the subsequent disturbance of Ca2+ homeostasis, cellular damage, and death. Conclusion: These observations support the view that both oxidative stress and intracellular Ca2+-overload play a critical role in mitochondrial disruption during the pathogenesis of different cardiac pathologies. Full article
(This article belongs to the Special Issue Mitochondrial Dysfunction and Oxidative Stress)
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10 pages, 3865 KiB  
Communication
Defective Mitochondrial Respiration in Hereditary Thoracic Aneurysms
by Daniel Marcos-Ríos, Antonio Rochano-Ortiz, Nerea Méndez-Barbero and Jorge Oller
Cells 2025, 14(11), 768; https://doi.org/10.3390/cells14110768 - 23 May 2025
Cited by 1 | Viewed by 628
Abstract
Thoracic aortic aneurysms are life-threatening vascular conditions linked to inherited disorders such as Marfan syndrome, Loeys–Dietz syndrome, vascular Ehlers–Danlos syndrome, and familial thoracic aortic aneurysms and dissections. While traditionally associated with the extracellular matrix and contractile defects in vascular smooth muscle cells, emerging [...] Read more.
Thoracic aortic aneurysms are life-threatening vascular conditions linked to inherited disorders such as Marfan syndrome, Loeys–Dietz syndrome, vascular Ehlers–Danlos syndrome, and familial thoracic aortic aneurysms and dissections. While traditionally associated with the extracellular matrix and contractile defects in vascular smooth muscle cells, emerging evidence suggests the key role of mitochondrial dysfunction. Here, we show that the overexpression of ACTA2R179H and TGFBR2G357W in murine aortic VSMCs reduces Mitochondrial Transcription Factor A (Tfam) expression, decreases mitochondrial DNA (mtDNA) content, and impairs oxidative phosphorylation, shifting metabolism toward glycolysis. Notably, nicotinamide riboside, a NAD+ precursor, restores mitochondrial respiration, increases Tfam and mtDNA levels, and promotes a contractile phenotype by enhancing actin polymerization and reducing matrix metalloproteinase activity. These findings identify mitochondrial dysfunction as a shared feature in hereditary thoracic aortic aneurysm, not only in Marfan syndrome, but also in other genetic forms, and highlight mitochondrial boosters as a potential therapeutic strategy. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Marfan Syndrome)
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25 pages, 14355 KiB  
Article
The Interaction Between the asb5a and asb5b Subtypes Jointly Regulates the L-R Asymmetrical Development of the Heart in Zebrafish
by Wanbang Zhou, Wanwan Cai, Yongqing Li, Luoqing Gao, Xin Liu, Siyuan Liu, Junrong Lei, Jisheng Zhang, Yuequn Wang, Zhigang Jiang, Xiushan Wu, Xiongwei Fan, Fang Li, Lan Zheng and Wuzhou Yuan
Int. J. Mol. Sci. 2025, 26(6), 2765; https://doi.org/10.3390/ijms26062765 - 19 Mar 2025
Viewed by 618
Abstract
The asb5 gene, a member of the Asb protein subfamily characterized by six ankyrin repeat domains, is highly conserved and comprises two subtypes, asb5a and asb5b, in zebrafish. Our previous research has demonstrated that a deficiency of the asb5 gene significantly [...] Read more.
The asb5 gene, a member of the Asb protein subfamily characterized by six ankyrin repeat domains, is highly conserved and comprises two subtypes, asb5a and asb5b, in zebrafish. Our previous research has demonstrated that a deficiency of the asb5 gene significantly impairs early cardiac contractile function, highlighting its close relationship with heart development. Zebrafish asb5 expression was disrupted by both morpholino (MO) antisense oligomer-mediated knockdown and a CRISPR-Cas9 system. A high-throughput RNA-Seq analysis was used to analyze the possible molecular regulatory mechanism of asb5 gene deletion leading to left–right (L-R) asymmetry defects in the heart. Whole-mount in situ hybridization (WISH) was conducted to evaluate gene expression patterns of Nodal signaling components and the positions of heart organs. Heart looping was defective in zebrafish asb5 morphants. Rescue experiments in the asb5-deficiency group (inactivating both asb5a and asb5b) demonstrated that the injection of either asb5a-mRNA or asb5b-mRNA alone was insufficient to rectify the abnormal L-R asymmetry of the heart. In contrast, the simultaneous injection of both asb5a-mRNA and asb5b-mRNA successfully rescued the morphological phenotype. A high-throughput RNA-Seq analysis of embryos at 48 h post fertilization (hpf) revealed that numerous genes associated with L-R asymmetry exhibited expression imbalances in the asb5-deficiency group. WISH further confirmed that the expression of genes such as fli1a, acta1b, hand2, has2, prrx1a, notch1b, and foxa3 were upregulated, while the expression of mei2a and tal1 was downregulated. These results indicated that loss of the asb5 gene in zebrafish led to the disordered development of L-R asymmetry in the heart, resulting in an imbalance in the expression of genes associated with the regulation of L-R asymmetry. Subsequently, we examined the expression patterns of classical Nodal signaling pathway-related genes using WISH. The results showed that the midline barrier factor gene lefty1 was downregulated at early stages in the asb5-deficiency group, and the expression of spaw and lefty2, which are specific to the left lateral plate mesoderm (LPM), was disrupted. This study reveals that the two subtypes of the asb5 gene in zebrafish, asb5a and asb5b, interact and jointly regulate the establishment of early cardiac L-R asymmetry through the Nodal-spaw-lefty signaling pathway. Full article
(This article belongs to the Section Molecular Biology)
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64 pages, 3040 KiB  
Review
Molecular Mechanisms Underlying Heart Failure and Their Therapeutic Potential
by Oveena Fonseka, Sanskruti Ravindra Gare, Xinyi Chen, Jiayan Zhang, Nasser Hawimel Alatawi, Claire Ross and Wei Liu
Cells 2025, 14(5), 324; https://doi.org/10.3390/cells14050324 - 20 Feb 2025
Cited by 5 | Viewed by 2987
Abstract
Heart failure (HF) is a prominent fatal cardiovascular disorder afflicting 3.4% of the adult population despite the advancement of treatment options. Therefore, a better understanding of the pathogenesis of HF is essential for exploring novel therapeutic strategies. Hypertrophy and fibrosis are significant characteristics [...] Read more.
Heart failure (HF) is a prominent fatal cardiovascular disorder afflicting 3.4% of the adult population despite the advancement of treatment options. Therefore, a better understanding of the pathogenesis of HF is essential for exploring novel therapeutic strategies. Hypertrophy and fibrosis are significant characteristics of pathological cardiac remodeling, contributing to HF. The mechanisms involved in the development of cardiac remodeling and consequent HF are multifactorial, and in this review, the key underlying mechanisms are discussed. These have been divided into the following categories thusly: (i) mitochondrial dysfunction, including defective dynamics, energy production, and oxidative stress; (ii) cardiac lipotoxicity; (iii) maladaptive endoplasmic reticulum (ER) stress; (iv) impaired autophagy; (v) cardiac inflammatory responses; (vi) programmed cell death, including apoptosis, pyroptosis, and ferroptosis; (vii) endothelial dysfunction; and (viii) defective cardiac contractility. Preclinical data suggest that there is merit in targeting the identified pathways; however, their clinical implications and outcomes regarding treating HF need further investigation in the future. Herein, we introduce the molecular mechanisms pivotal in the onset and progression of HF, as well as compounds targeting the related mechanisms and their therapeutic potential in preventing or rescuing HF. This, therefore, offers an avenue for the design and discovery of novel therapies for the treatment of HF. Full article
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19 pages, 20178 KiB  
Article
Cardiac MRI Strain as an Early Indicator of Myocardial Dysfunction in Hypertrophic Cardiomyopathy
by Siqin Liu, Oumaima Laghzali, Shahriar Shalikar, Mara-Camelia Rusu, Lucie Carrier, Thoralf Niendorf and Min-Chi Ku
Int. J. Mol. Sci. 2025, 26(4), 1407; https://doi.org/10.3390/ijms26041407 - 7 Feb 2025
Cited by 3 | Viewed by 1229
Abstract
Hypertrophic cardiomyopathy (HCM) is often characterized by augmented cardiac contractility, which frequently remains undetectable in its early stages. Emerging evidence suggests that hypercontractility is linked to mitochondrial defects that develop early in HCM progression. However, imaging markers for identifying these early alterations in [...] Read more.
Hypertrophic cardiomyopathy (HCM) is often characterized by augmented cardiac contractility, which frequently remains undetectable in its early stages. Emerging evidence suggests that hypercontractility is linked to mitochondrial defects that develop early in HCM progression. However, imaging markers for identifying these early alterations in myocardial function are lacking. We used cardiac magnetic resonance feature tracking (CMR-FT) to assess myocardial strain in a Mybpc3-knockin (KI) mouse model that mimicked human HCM. While homozygous (HOM) mice exhibited cardiac hypertrophy, heterozygous (HET) mice represented an early, asymptomatic stage of HCM. To explore mitochondrial contributions to hypercontractility, we evaluated mitochondrial integrity via scanning electron microscopy (SEM) and correlated these findings with strain abnormalities. Young HET female, but not male mice exhibited significant torsion abnormalities (p = 0.02), reduced left ventricular global longitudinal strain (LVGLS, p = 0.009), and impaired right ventricular global longitudinal strain (RVGLS, p = 0.035) compared to the controls. Strain abnormalities correlated strongly with mitochondrial morphological alterations, including changes in volume and area distribution (R > 0.7). Abnormal myocardial strain patterns, including torsion and GLS, serve as early markers of HCM and are closely associated with underlying mitochondrial dysfunction. The HET Mybpc3-KI HCM model provides important insights into the initial stages of HCM progression, highlighting strain abnormalities and sex-specific differences to enhance early diagnosis and therapeutic strategies. Full article
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22 pages, 2440 KiB  
Review
Cardiotoxicity of Chemotherapy: A Multi-OMIC Perspective
by Yan Ma, Mandy O. J. Grootaert and Raj N. Sewduth
J. Xenobiot. 2025, 15(1), 9; https://doi.org/10.3390/jox15010009 - 8 Jan 2025
Viewed by 2653
Abstract
Chemotherapy-induced cardiotoxicity is a critical issue in cardio-oncology, as cancer treatments often lead to severe cardiovascular complications. Approximately 10% of cancer patients succumb to cardiovascular problems, with lung cancer patients frequently experiencing arrhythmias, cardiac failure, tamponade, and cardiac metastasis. The cardiotoxic effects of [...] Read more.
Chemotherapy-induced cardiotoxicity is a critical issue in cardio-oncology, as cancer treatments often lead to severe cardiovascular complications. Approximately 10% of cancer patients succumb to cardiovascular problems, with lung cancer patients frequently experiencing arrhythmias, cardiac failure, tamponade, and cardiac metastasis. The cardiotoxic effects of anti-cancer treatments manifest at both cellular and tissue levels, causing deformation of cardiomyocytes, leading to contractility issues and fibrosis. Repeated irradiation and chemotherapy increase the risk of valvular, pericardial, or myocardial diseases. Multi-OMICs analyses reveal that targeting specific pathways as well as specific protein modifications, such as ubiquitination and phosphorylation, could offer potential therapeutic alternatives to current treatments, including Angiotensin converting enzymes (ACE) inhibitors and beta-blockers that mitigate symptoms but do not prevent cardiomyocyte death, highlighting the need for more effective therapies to manage cardiovascular defects in cancer survivors. This review explores the xenobiotic nature of chemotherapy agents and their impact on cardiovascular health, aiming to identify novel biomarkers and therapeutic targets to mitigate cardiotoxicity. Full article
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8 pages, 221 KiB  
Article
Left Atrial Structural and Functional Changes in Adults with Congenital Septal Defects and Paroxysmal Atrial Fibrillation
by Anton V. Minaev, Marina Yu. Mironenko, Vera I. Dontsova, Yulia D. Pirushkina, Bektur Sh. Berdibekov, Alexander S. Voynov, Julia A. Sarkisyan and Elena Z. Golukhova
J. Clin. Med. 2024, 13(19), 6023; https://doi.org/10.3390/jcm13196023 - 9 Oct 2024
Viewed by 1205
Abstract
Aims. To identify the difference between adult patients with septal defects and paroxysmal atrial fibrillation (AF) and patients without a history of arrhythmia using the left atrial (LA) volume and function parameters, to reveal the parameters associated with AF development. Methods and [...] Read more.
Aims. To identify the difference between adult patients with septal defects and paroxysmal atrial fibrillation (AF) and patients without a history of arrhythmia using the left atrial (LA) volume and function parameters, to reveal the parameters associated with AF development. Methods and results. In this prospective study, 81 patients with septal defects and left-to-right shunts were enrolled between 2021 and 2023 and divided into two groups: with paroxysmal AF and without AF. Left atrial function was analyzed based on the indexed left atrial volumes (LAVI and preA-LAVI), ejection fraction (LAEF), expansion index (LAEI), reservoir (LAS-r), conduit (LAS-cd) and contractile (LAS-ct) strain, and stiffness index (LASI) using a Philips CVx3D ultrasound system (Philips, Amsterdam, The Netherlands) and corresponding software. In total, 26 patients with paroxysmal atrial fibrillation (mean age: 59.6 ± 11.7 years, female: 80.8%) and 55 patients with septal defects without any history of arrhythmias (mean age: 44.8 ± 11.6 years, female: 81.8%) were included. All patients were in the NYHA class I or II at baseline. Our findings demonstrated a significant difference between all LA function parameters in the two groups. Upon univariable analysis, the LAVI, preA-LAVI, LASI, LAEF, LAEI, LAS-r, LAS-c, LAS-ct, age, cardiac index, E/A, and RV pressure were found to be associated with AF. The multivariate analysis identified LAVI (OR 1.236, 95% CI 1.022–1.494, p = 0.03), LAS-r (OR 0.723, 95% CI 0.556–0.940, p = 0.02), and LAS-ct (OR 1.518, 95% CI 1.225–1.880, p < 0.001) as independent predictors of AF development. The proposed model demonstrated high sensitivity and specificity with an adjusted classification threshold of 0.38 (AUC: 0.97, 95% CI 0.93–1.00, sensitivity 92% and specificity 92%, p < 0.001). Conclusions. The assessment of LA function using speckle-tracking echocardiography demonstrated significantly different values in the AF group among patients with congenital septal defects. This technique can therefore be implemented in routine clinical management. The key message. Atrial fibrillation development in adult patients with congenital septal defects and a left-to-right shunt is associated with the changes in left atrial function under conditions of an increased preload. Full article
16 pages, 1092 KiB  
Review
Myotube Guidance: Shaping up the Musculoskeletal System
by Aaron N. Johnson
J. Dev. Biol. 2024, 12(3), 25; https://doi.org/10.3390/jdb12030025 - 17 Sep 2024
Viewed by 2094
Abstract
Myofibers are highly specialized contractile cells of skeletal muscles, and dysregulation of myofiber morphogenesis is emerging as a contributing cause of myopathies and structural birth defects. Myotubes are the myofiber precursors and undergo a dramatic morphological transition into long bipolar myofibers that are [...] Read more.
Myofibers are highly specialized contractile cells of skeletal muscles, and dysregulation of myofiber morphogenesis is emerging as a contributing cause of myopathies and structural birth defects. Myotubes are the myofiber precursors and undergo a dramatic morphological transition into long bipolar myofibers that are attached to tendons on two ends. Similar to axon growth cones, myotube leading edges navigate toward target cells and form cell–cell connections. The process of myotube guidance connects myotubes with the correct tendons, orients myofiber morphology with the overall body plan, and generates a functional musculoskeletal system. Navigational signaling, addition of mass and volume, and identification of target cells are common events in myotube guidance and axon guidance, but surprisingly, the mechanisms regulating these events are not completely overlapping in myotubes and axons. This review summarizes the strategies that have evolved to direct myotube leading edges to predetermined tendon cells and highlights key differences between myotube guidance and axon guidance. The association of myotube guidance pathways with developmental disorders is also discussed. Full article
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19 pages, 3210 KiB  
Article
The Impact of Extracellular Histones and Absence of Toll-like Receptors on Cardiac Functional and Electrical Disturbances in Mouse Hearts
by Randall Loaiza, Fatemeh Fattahi, Miriam Kalbitz, Jamison J. Grailer, Mark W. Russell, Jose Jalife, Hector H. Valdivia, Firas S. Zetoune and Peter A. Ward
Int. J. Mol. Sci. 2024, 25(16), 8653; https://doi.org/10.3390/ijms25168653 - 8 Aug 2024
Cited by 1 | Viewed by 1564
Abstract
In polymicrobial sepsis, the extracellular histones, mainly released from activated neutrophils, significantly contribute to cardiac dysfunction (septic cardiomyopathy), as demonstrated in our previous studies using Echo-Doppler measurements. This study aims to elucidate the roles of extracellular histones and their interactions with Toll-like receptors [...] Read more.
In polymicrobial sepsis, the extracellular histones, mainly released from activated neutrophils, significantly contribute to cardiac dysfunction (septic cardiomyopathy), as demonstrated in our previous studies using Echo-Doppler measurements. This study aims to elucidate the roles of extracellular histones and their interactions with Toll-like receptors (TLRs) in cardiac dysfunction. Through ex vivo assessments of ECG, left ventricle (LV) function parameters, and in vivo Echo-Doppler studies in mice perfused with extracellular histones, we aim to provide comprehensive insights into the mechanisms underlying sepsis-induced cardiac dysfunction. Langendorff-perfused hearts from both wild-type and TLR2, TLR3, or TLR4 knockout (KO) mice were examined. Paced mouse hearts were perfused with histones to assess contractility and relaxation. Echo-Doppler studies evaluated cardiac dysfunction after intravenous histone injection. Histone perfusion caused defects in contractility and relaxation, with TLR2 and TLR3 KO mice being partially protected. Specifically, TLR2 KO mice exhibited the greatest reduction in Echo-Doppler abnormalities, while TLR4 KO exacerbated cardiac dysfunction. Among individual histones, H1 induced the most pronounced abnormalities in cardiac function, apoptosis of cardiomyocytes, and LDH release. Our data highlight significant interactions between histones and TLRs, providing insights into histones especially H1 as potential therapeutic targets for septic cardiomyopathy. Further studies are needed to explore specific histone–TLR interactions and their mechanisms. Full article
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21 pages, 1602 KiB  
Review
Molecular Basis of Cardiomyopathies in Type 2 Diabetes
by Silvia Giardinelli, Giovanni Meliota, Donatella Mentino, Gabriele D’Amato and Maria Felicia Faienza
Int. J. Mol. Sci. 2024, 25(15), 8280; https://doi.org/10.3390/ijms25158280 - 29 Jul 2024
Cited by 2 | Viewed by 3319
Abstract
Diabetic cardiomyopathy (DbCM) is a common complication in individuals with type 2 diabetes mellitus (T2DM), and its exact pathogenesis is still debated. It was hypothesized that chronic hyperglycemia and insulin resistance activate critical cellular pathways that are responsible for numerous functional and anatomical [...] Read more.
Diabetic cardiomyopathy (DbCM) is a common complication in individuals with type 2 diabetes mellitus (T2DM), and its exact pathogenesis is still debated. It was hypothesized that chronic hyperglycemia and insulin resistance activate critical cellular pathways that are responsible for numerous functional and anatomical perturbations in the heart. Interstitial inflammation, oxidative stress, myocardial apoptosis, mitochondria dysfunction, defective cardiac metabolism, cardiac remodeling, hypertrophy and fibrosis with consequent impaired contractility are the most common mechanisms implicated. Epigenetic changes also have an emerging role in the regulation of these crucial pathways. The aim of this review was to highlight the increasing knowledge on the molecular mechanisms of DbCM and the new therapies targeting specific pathways. Full article
(This article belongs to the Special Issue Advances in Molecular Research of Diabetic Cardiomyopathy)
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20 pages, 12815 KiB  
Article
GRAF1 Acts as a Downstream Mediator of Parkin to Regulate Mitophagy in Cardiomyocytes
by Qiang Zhu, Matthew E. Combs, Dawn E. Bowles, Ryan T. Gross, Michelle Mendiola Pla, Christopher P. Mack and Joan M. Taylor
Cells 2024, 13(5), 448; https://doi.org/10.3390/cells13050448 - 4 Mar 2024
Cited by 1 | Viewed by 3099
Abstract
Cardiomyocytes rely on proper mitochondrial homeostasis to maintain contractility and achieve optimal cardiac performance. Mitochondrial homeostasis is controlled by mitochondrial fission, fusion, and mitochondrial autophagy (mitophagy). Mitophagy plays a particularly important role in promoting the degradation of dysfunctional mitochondria in terminally differentiated cells. [...] Read more.
Cardiomyocytes rely on proper mitochondrial homeostasis to maintain contractility and achieve optimal cardiac performance. Mitochondrial homeostasis is controlled by mitochondrial fission, fusion, and mitochondrial autophagy (mitophagy). Mitophagy plays a particularly important role in promoting the degradation of dysfunctional mitochondria in terminally differentiated cells. However, the precise mechanisms by which this is achieved in cardiomyocytes remain opaque. Our study identifies GRAF1 as an important mediator in PINK1-Parkin pathway-dependent mitophagy. Depletion of GRAF1 (Arhgap26) in cardiomyocytes results in actin remodeling defects, suboptimal mitochondria clustering, and clearance. Mechanistically, GRAF1 promotes Parkin-LC3 complex formation and directs autophagosomes to damaged mitochondria. Herein, we found that these functions are regulated, at least in part, by the direct binding of GRAF1 to phosphoinositides (PI(3)P, PI(4)P, and PI(5)P) on autophagosomes. In addition, PINK1-dependent phosphorylation of Parkin promotes Parkin-GRAF1-LC3 complex formation, and PINK1-dependent phosphorylation of GRAF1 (on S668 and S671) facilitates the clustering and clearance of mitochondria. Herein, we developed new phosphor-specific antibodies to these sites and showed that these post-translational modifications are differentially modified in human hypertrophic cardiomyopathy and dilated cardiomyopathy. Furthermore, our metabolic studies using serum collected from isoproterenol-treated WT and GRAF1CKO mice revealed defects in mitophagy-dependent cardiomyocyte fuel flexibility that have widespread impacts on systemic metabolism. In summary, our study reveals that GRAF1 co-regulates actin and membrane dynamics to promote cardiomyocyte mitophagy and that dysregulation of GRAF1 post-translational modifications may underlie cardiac disease pathogenesis. Full article
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12 pages, 1784 KiB  
Review
Processes Controlling the Contractile Ring during Cytokinesis in Fission Yeast, Including the Role of ESCRT Proteins
by Imane M. Rezig, Wandiahyel G. Yaduma and Christopher J. McInerny
J. Fungi 2024, 10(2), 154; https://doi.org/10.3390/jof10020154 - 15 Feb 2024
Viewed by 2447
Abstract
Cytokinesis, as the last stage of the cell division cycle, is a tightly controlled process amongst all eukaryotes, with defective division leading to severe cellular consequences and implicated in serious human diseases and conditions such as cancer. Both mammalian cells and the fission [...] Read more.
Cytokinesis, as the last stage of the cell division cycle, is a tightly controlled process amongst all eukaryotes, with defective division leading to severe cellular consequences and implicated in serious human diseases and conditions such as cancer. Both mammalian cells and the fission yeast Schizosaccharomyces pombe use binary fission to divide into two equally sized daughter cells. Similar to mammalian cells, in S. pombe, cytokinetic division is driven by the assembly of an actomyosin contractile ring (ACR) at the cell equator between the two cell tips. The ACR is composed of a complex network of membrane scaffold proteins, actin filaments, myosin motors and other cytokinesis regulators. The contraction of the ACR leads to the formation of a cleavage furrow which is severed by the endosomal sorting complex required for transport (ESCRT) proteins, leading to the final cell separation during the last stage of cytokinesis, the abscission. This review describes recent findings defining the two phases of cytokinesis in S. pombe: ACR assembly and constriction, and their coordination with septation. In summary, we provide an overview of the current understanding of the mechanisms regulating ACR-mediated cytokinesis in S. pombe and emphasize a potential role of ESCRT proteins in this process. Full article
(This article belongs to the Special Issue Yeast Cytokinesis)
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22 pages, 1884 KiB  
Review
Smooth Muscle Heterogeneity and Plasticity in Health and Aortic Aneurysmal Disease
by Yunwen Hu, Zhaohua Cai and Ben He
Int. J. Mol. Sci. 2023, 24(14), 11701; https://doi.org/10.3390/ijms241411701 - 20 Jul 2023
Cited by 20 | Viewed by 4237
Abstract
Vascular smooth muscle cells (VSMCs) are the predominant cell type in the medial layer of the aorta, which plays a critical role in the maintenance of aortic wall integrity. VSMCs have been suggested to have contractile and synthetic phenotypes and undergo phenotypic switching [...] Read more.
Vascular smooth muscle cells (VSMCs) are the predominant cell type in the medial layer of the aorta, which plays a critical role in the maintenance of aortic wall integrity. VSMCs have been suggested to have contractile and synthetic phenotypes and undergo phenotypic switching to contribute to the deteriorating aortic wall structure. Recently, the unprecedented heterogeneity and diversity of VSMCs and their complex relationship to aortic aneurysms (AAs) have been revealed by high-resolution research methods, such as lineage tracing and single-cell RNA sequencing. The aortic wall consists of VSMCs from different embryonic origins that respond unevenly to genetic defects that directly or indirectly regulate VSMC contractile phenotype. This difference predisposes to hereditary AAs in the aortic root and ascending aorta. Several VSMC phenotypes with different functions, for example, secreting VSMCs, proliferative VSMCs, mesenchymal stem cell-like VSMCs, immune-related VSMCs, proinflammatory VSMCs, senescent VSMCs, and stressed VSMCs are identified in non-hereditary AAs. The transformation of VSMCs into different phenotypes is an adaptive response to deleterious stimuli but can also trigger pathological remodeling that exacerbates the pathogenesis and development of AAs. This review is intended to contribute to the understanding of VSMC diversity in health and aneurysmal diseases. Papers that give an update on VSMC phenotype diversity in health and aneurysmal disease are summarized and recent insights on the role of VSMCs in AAs are discussed. Full article
(This article belongs to the Special Issue New Trends in Diabetes, Hypertension and Cardiovascular Diseases)
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