Molecular Mechanisms of Cardiac Remodeling and Regeneration in Physical Exercise

Regular physical activity with aerobic and muscle-strengthening training protects against the occurrence and progression of cardiovascular disease and can improve cardiac function in heart failure patients. In the past decade significant advances have been made in identifying mechanisms of cardiomyocyte re-programming and renewal including an enhanced exercise-induced proliferational capacity of cardiomyocytes and its progenitor cells. Various intracellular mechanisms mediating these positive effects on cardiac function have been found in animal models of exercise and will be highlighted in this review. 1) activation of extracellular and intracellular signaling pathways including phosphatidylinositol 3 phosphate kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR), EGFR/JNK/SP-1, nitric oxide (NO)-signaling, and extracellular vesicles; 2) gene expression modulation via microRNAs (miR), in particular via miR-17-3p and miR-222; and 3) modulation of cardiac cellular metabolism and mitochondrial adaption. Understanding the cellular mechanisms, which generate an exercise-induced cardioprotective cellular phenotype with physiological hypertrophy and enhanced proliferational capacity may give rise to novel therapeutic targets. These may open up innovative strategies to preserve cardiac function after myocardial injury as well as in aged cardiac tissue.

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Antioxidant and Anti-inflammatory Mechanisms of Astaxanthin in Cardiovascular Diseases

10.20944/preprints202008.0119.v1 ◽

2020 ◽

Author(s):

Carolina Parga Martins Pereira ◽

Ana Carolina Remondi Souza ◽

Andrea Rodrigues Vasconcelos ◽

Pietra Sacramento Prado ◽

José João Name

Keyword(s):

Cardiovascular Diseases ◽

Molecular Mechanisms ◽

Cardiovascular Health ◽

Redox Balance ◽

Cellular Mechanisms ◽

Positive Effects ◽

Antioxidant Agents ◽

Therapeutic Properties ◽

Anti Inflammatory ◽

Preclinical And Clinical Studies

Cardiovascular disease is the most common cause of death. Oxidative stress and inflammation are pathophysiological processes involved in the development of cardiovascular diseases, so anti-inflammatory and antioxidant agents that modulate redox balance have become the targets of research to evaluate their molecular mechanisms and therapeutic properties. Astaxanthin, a carotenoid of the xanthophyll group, has potent antioxidant effects due to its molecular structure and its arrangement in the plasma membrane, factors that favor the neutralization of reactive oxygen and nitrogen species. This carotenoid also stands out for its anti-inflammatory activity, possibly interrelated with its antioxidant effect, as well as for its modulation of lipid and glucose metabolism. Considering the potential positive effects of astaxanthin on cardiovascular health evidenced by preclinical and clinical studies, this paper describes the molecular and cellular mechanisms related to the antioxidant and anti-inflammatory properties of this carotenoid in cardiovascular diseases, especially atherosclerosis.

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Long-term treadmill exercise induces neuroprotective molecular changes in rat brain

Journal of Applied Physiology ◽

10.1152/japplphysiol.00425.2011 ◽

2011 ◽

Vol 111 (5) ◽

pp. 1380-1390 ◽

Cited By ~ 55

Author(s):

S. Bayod ◽

J. del Valle ◽

A. M. Canudas ◽

J. F. Lalanza ◽

S. Sanchez-Roige ◽

...

Keyword(s):

Treadmill Training ◽

Sirtuin 1 ◽

Male Rat ◽

Cellular Mechanisms ◽

Neuroprotective Effects ◽

Positive Effects ◽

Oxphos System ◽

Adult Male Rat ◽

Exercise Induced

Exercise enhances general health. However, its effects on neurodegeneration are controversial, and the molecular pathways in the brain involved in this enhancement are poorly understood. Here, we examined the effect of long-term moderate treadmill training on adult male rat cortex and hippocampus to identify the cellular mechanisms behind the effects of exercise. We compared three animal groups: exercised (30 min/day, 12 m/min, 5 days/wk, 36 wk), handled but nonexercised (treadmill handling procedure, 0 m/min), and sedentary (nonhandled and nonexercised). Moderate long-term exercise induced an increase in IGF-1 levels and also in energy parameters, such as PGC-1α and the OXPHOS system. Moreover, the sirtuin 1 pathway was activated in both the exercised and nonexercised groups but not in sedentary rats. This induction could be a consequence of exercise as well as the handling procedure. To determine whether the long-term moderate treadmill training had neuroprotective effects, we studied tau hyperphosphorylation and GSK3β activation. Our results showed reduced levels of phospho-tau and GSK3β activation mainly in the hippocampus of the exercised animals. In conclusion, in our rodent model, exercise improved several major brain parameters, especially in the hippocampus. These improvements induced the upregulation of sirtuin 1, a protein that extends life, the stimulation of mitochondrial biogenesis, the activation of AMPK, and the prevention of signs of neurodegeneration. These findings are consistent with other reports showing that physical exercise has positive effects on hormesis.

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Intracellular Signaling Pathways and Size, Shape, and Rupture History of Human Intracranial Aneurysms

Neurosurgery ◽

10.1227/neu.0b013e31824c057e ◽

2012 ◽

Vol 70 (6) ◽

pp. 1565-1573 ◽

Cited By ~ 16

Author(s):

Elisa Laaksamo ◽

Manasi Ramachandran ◽

Juhana Frösen ◽

Riikka Tulamo ◽

Marc Baumann ◽

...

Keyword(s):

Intracellular Signaling ◽

Mammalian Target Of Rapamycin ◽

Morphological Features ◽

Cellular Mechanisms ◽

3 Dimensional ◽

Extracellular Signal ◽

Mitogen Activated Protein ◽

Element Binding Protein ◽

Angiographic Data ◽

History Of

Abstract BACKGROUND: Size and morphological features are associated with intracranial aneurysm (IA) rupture. The cellular mechanisms of IA development and rupture are poorly known. OBJECTIVE: We studied the expression and phosphorylation of different intracellular signaling molecules in the IA wall compared with IA morphological features to understand better the cellular pathways involved in IA development and wall degeneration. METHODS: Nine ruptured and 17 unruptured human IA samples were collected intraoperatively. The expression levels and phosphorylation state of 3 mitogen-activated protein kinases (c-Jun N-terminal kinase [JNK], p38, extracellular signal-regulated kinase [ERK]), Bcl-2 antagonist of cell death (Bad), mammalian target of rapamycin (mTOR), cyclic AMP response element binding protein (CREB), and Akt were determined by Western blotting. The localization of signaling proteins was determined by immunofluorescence. From 3-dimensional segmentation of computed tomography angiographic data, size and shape indexes were calculated. RESULTS: We found a 5-fold difference in phospho-Bad levels between ruptured and unruptured IAs. Phospho-mTOR was downregulated 2.5-fold in ruptured IAs. Phospho-p54 JNK, phospho-p38, and phospho-Akt levels correlated positively with IA size. Phospho-CREB levels were significantly associated with nonsphericity and ellipticity indexes. Phospho-Akt and phospho-p38 correlated negatively with undulation index. CONCLUSION: The signaling pathway profile (apoptosis, cell proliferation, stress signaling) differs between ruptured and unruptured IAs and is associated with IA geometry. Our results increase the knowledge of IA development and wall degeneration.

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Abstract MP170: Increased Ga o Expression Regulated by NRSF Plays a Key Role in the Development of Heart Failure Through the Impairment of Ca 2+ Homeostasis

Circulation Research ◽

10.1161/res.127.suppl_1.mp170 ◽

2020 ◽

Vol 127 (Suppl_1) ◽

Author(s):

Hideaki Inazumi ◽

Yasuaki Nakagawa ◽

Kenji Moriuchi ◽

Koichiro Kuwahara

Keyword(s):

Heart Failure ◽

Cardiac Function ◽

Cardiac Dysfunction ◽

Intracellular Signaling ◽

Molecular Mechanisms ◽

Troponin T ◽

Dominant Negative ◽

Dominant Negative Mutant ◽

Cardiac Gene ◽

Normal Cardiac Function

Background: In the development of heart failure, pathological intracellular signaling reactivates fetal cardiac gene program, which leads to pathological cardiac remodeling. We previously reported that a transcriptional repressor, neuron restrictive silencer factor (NRSF) represses fetal cardiac gene program and maintains normal cardiac function, while pathological stimuli de-repress this NRSF mediated repression via activation of CaMKII. Molecular mechanisms by which NRSF maintains cardiac function remains to be determined, however. Purpose: To elucidate molecular mechanisms by which NRSF maintains normal cardiac function. Methods and Results: Newly generated cardiac-specific NRSF knockout mice (NRSF-cKO) showed cardiac dysfunction and premature deaths accompanied with lethal arrhythmias, as was observed in our previously reported cardiac-specific dominant-negative mutant of NRSF transgenic mice (dnNRSF-Tg). Expression of Gnao1 gene encoding Gα o , a member of inhibitory G proteins, was commonly increased in ventricles of dnNRSF-Tg and NRSF-cKO. ChIP-seq analysis, reporter assay and electrophoretic mobility shift assay identified that NRSF transcriptionally regulates Gnao1 gene expression. Genetic Knockdown of Gα o in dnNRSF-Tg and NRSF-cKO ameliorated the reduced systolic function, increased arrhythmogenicity and reduced survival rates. Conversely cardiac-specific GNAO1 overexpression was sufficient to show impaired cardiac function. Mechanistically, Gα o increases current density in surface sarcolemmal L-type Ca 2 + channel and then activates CaMKII without affecting protein kinase A activity, which finally leads to impaired Ca 2+ handling and systolic dysfunction. Furthermore, expression of Gα o is also increased in ventricles of transverse aortic constriction model mice and cardiac troponin T mutant DCM model mice, in both of which, genetic reduction of Gα o prevented the progression of cardiac dysfunction. Conclusions: Increased expression of Gα o , induced by attenuation of NRSF-mediated repression forms a pathological circuit via activation of CaMKII and progresses heart failure by impairing Ca 2+ homeostasis. Gα o is a potential therapeutic target for heart failure.

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The Molecular Mechanisms Associated with Aerobic Exercise-Induced Cardiac Regeneration

Biomolecules ◽

10.3390/biom11010019 ◽

2020 ◽

Vol 11 (1) ◽

pp. 19

Author(s):

Bing Bo ◽

Yang Zhou ◽

Qingyun Zheng ◽

Guandong Wang ◽

Ke Zhou ◽

...

Keyword(s):

Aerobic Exercise ◽

Molecular Mechanisms ◽

Heart Function ◽

Cardiac Regeneration ◽

Cell Loss ◽

Myocardial Cell ◽

Cellular Mechanisms ◽

Paracrine Factors ◽

Ability To Regenerate ◽

Exercise Induced

The leading cause of heart failure is cardiomyopathy and damage to the cardiomyocytes. Adult mammalian cardiomyocytes have the ability to regenerate, but this cannot wholly compensate for myocardial cell loss after myocardial injury. Studies have shown that exercise has a regulatory role in the activation and promotion of regeneration of healthy and injured adult cardiomyocytes. However, current research on the effects of aerobic exercise in myocardial regeneration is not comprehensive. This review discusses the relationships between aerobic exercise and the regeneration of cardiomyocytes with respect to complex molecular and cellular mechanisms, paracrine factors, transcriptional factors, signaling pathways, and microRNAs that induce cardiac regeneration. The topics discussed herein provide a knowledge base for physical activity-induced cardiomyocyte regeneration, in which exercise enhances overall heart function and improves the efficacy of cardiac rehabilitation.

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Intestinal Fructose and Glucose Metabolism in Health and Disease

Nutrients ◽

10.3390/nu12010094 ◽

2019 ◽

Vol 12 (1) ◽

pp. 94 ◽

Cited By ~ 7

Author(s):

Beatriz Merino ◽

Cristina M. Fernández-Díaz ◽

Irene Cózar-Castellano ◽

German Perdomo

Keyword(s):

Glucose Metabolism ◽

Intracellular Signaling ◽

Molecular Mechanisms ◽

Metabolic Diseases ◽

Sugar Metabolism ◽

Sugar Consumption ◽

Cellular Mechanisms ◽

Obesity And Diabetes ◽

Health And Disease ◽

Dietary Sugars

The worldwide epidemics of obesity and diabetes have been linked to increased sugar consumption in humans. Here, we review fructose and glucose metabolism, as well as potential molecular mechanisms by which excessive sugar consumption is associated to metabolic diseases and insulin resistance in humans. To this end, we focus on understanding molecular and cellular mechanisms of fructose and glucose transport and sensing in the intestine, the intracellular signaling effects of dietary sugar metabolism, and its impact on glucose homeostasis in health and disease. Finally, the peripheral and central effects of dietary sugars on the gut–brain axis will be reviewed.

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Parathyroid Hormone in the Regulation of Bone Growth and Resorption in Health and Disease

Annals of the Russian academy of medical sciences ◽

10.15690/vramn1440 ◽

2021 ◽

Vol 76 (5) ◽

pp. 506-517

Author(s):

Maria V. Vorontsova ◽

Konstantin Y. Kulebyakin ◽

Nadezhda V. Makazan ◽

Leila S. Sozaeva ◽

Pyotr A. Tyurin-Kuzmin

Keyword(s):

Parathyroid Hormone ◽

Bone Tissue ◽

Intracellular Signaling ◽

Molecular Mechanisms ◽

Bone Growth ◽

The Body ◽

Signaling Cascades ◽

Main Body ◽

Bone Homeostasis ◽

Cellular Mechanisms

Parathyroid hormone (PTH) is a key hormone responsible for regulation of calcium homeostasis in the body. Since the main body calcium depot is bone tissue, PTH has a decisive effect on its homeostasis. In this case, the hormone can activate both bone formation and resorption. Thus, PTH can ensure the conjugation of anabolic and catabolic processes, which is necessary for the renewal of bone tissue, which is had to function under constant mechanical stress. At the same time, the use of PTH in medical practice is rather small, despite its high potential as a basis for the treatment of various pathologies associated with impaired bone homeostasis. Presented review, describes the intracellular signaling cascades and molecular mechanisms that underlie the action of PTH on bone tissue cells, and intracellular signaling cascades are described. A separate section examines the cellular mechanisms of the action of PTH on bone homeostasis, discusses how the effect of the hormone on different types of cells provides an interface between the processes of synthesis and resorption. In addition, the review examines diseases associated with impaired bone homeostasis, as well as the role of PTH and impaired signaling in their etiology.

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Exercise biology of neuromuscular disorders

Applied Physiology Nutrition and Metabolism ◽

10.1139/apnm-2018-0229 ◽

2018 ◽

Vol 43 (11) ◽

pp. 1194-1206 ◽

Cited By ~ 7

Author(s):

Sean Y. Ng ◽

Alexander Manta ◽

Vladimir Ljubicic

Keyword(s):

Molecular Mechanisms ◽

Acute Exercise ◽

Muscular Atrophy ◽

Neuromuscular Disorders ◽

Neuromuscular System ◽

Cellular Mechanisms ◽

Disease Mechanisms ◽

Exercise Adaptation ◽

Exercise Induced

Neuromuscular disorders (NMDs) are chronic conditions that affect the neuromuscular system. Many NMDs currently have no cure; however, as more effective therapies become available for NMD patients, these individuals will exhibit improved health and/or prolonged lifespans. As a result, persons with NMDs will likely desire to engage in a more diverse variety of activities of daily living, including increased physical activity or exercise. Therefore, there is a need to increase our knowledge of the effects of acute exercise and chronic training on the neuromuscular system in NMD contexts. Here, we discuss the disease mechanisms and exercise biology of Duchenne muscular dystrophy (DMD), spinal muscular atrophy (SMA), and myotonic dystrophy type 1 (DM1), which are among the most prevalent NMDs in children and adults. Evidence from clinical and preclinical studies are reviewed, with emphasis on the functional outcomes of exercise, as well as on the putative cellular mechanisms that drive exercise-induced remodelling of the neuromuscular system. Continued investigation of the molecular mechanisms of exercise adaptation in DMD, SMA, and DM1 will assist in enhancing our understanding of the biology of these most prevalent NMDs. This information may also be useful for guiding the development of novel therapeutic targets for future pursuit.

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The Impact of Ultraviolet Radiation on Barrier Function in Human Skin: Molecular Mechanisms and Topical Therapeutics

Current Medicinal Chemistry ◽

10.2174/0929867324666171106164916 ◽

2019 ◽

Vol 25 (40) ◽

pp. 5503-5511 ◽

Cited By ~ 5

Author(s):

Abdulaziz Alhasaniah ◽

Michael J. Sherratt ◽

Catherine A. O'Neill

Keyword(s):

Ultraviolet Radiation ◽

Barrier Function ◽

Molecular Mechanisms ◽

Transepidermal Water Loss ◽

Protective Effects ◽

Barrier Dysfunction ◽

Epidermal Barrier ◽

Positive Effects ◽

Terrestrial Mammals ◽

The Impact

A competent epidermal barrier is crucial for terrestrial mammals. This barrier must keep in water and prevent entry of noxious stimuli. Most importantly, the epidermis must also be a barrier to ultraviolet radiation (UVR) from the sunlight. Currently, the effects of ultraviolet radiation on epidermal barrier function are poorly understood. However, studies in mice and more limited work in humans suggest that the epidermal barrier becomes more permeable, as measured by increased transepidermal water loss, in response UVR, at doses sufficiently high to induce erythema. The mechanisms may include disturbance in the organisation of lipids in the stratum corneum (the outermost layer of the epidermis) and reduction in tight junction function in the granular layer (the first living layer of the skin). By contrast, suberythemal doses of UVR appear to have positive effects on epidermal barrier function. Topical sunscreens have direct and indirect protective effects on the barrier through their ability to block UV and also due to their moisturising or occlusive effects, which trap water in the skin, respectively. Some topical agents such as specific botanical extracts have been shown to prevent the loss of water associated with high doses of UVR. In this review, we discuss the current literature and suggest that the biology of UVR-induced barrier dysfunction, and the use of topical products to protect the barrier, are areas worthy of further investigation.

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The Mechanisms Behind the Biological Activity of Flavonoids

Current Medicinal Chemistry ◽

10.2174/0929867325666180706104829 ◽

2019 ◽

Vol 26 (39) ◽

pp. 6976-6990 ◽

Cited By ~ 12

Author(s):

Ana María González-Paramás ◽

Begoña Ayuda-Durán ◽

Sofía Martínez ◽

Susana González-Manzano ◽

Celestino Santos-Buelga

Keyword(s):

Gene Expression ◽

Biological Activity ◽

Phenolic Compounds ◽

Intracellular Signaling ◽

Molecular Mechanisms ◽

Radical Scavenging ◽

Model Organism ◽

Stress Theory ◽

Radical Scavenging Properties

: Flavonoids are phenolic compounds widely distributed in the human diet. Their intake has been associated with a decreased risk of different diseases such as cancer, immune dysfunction or coronary heart disease. However, the knowledge about the mechanisms behind their in vivo activity is limited and still under discussion. For years, their bioactivity was associated with the direct antioxidant and radical scavenging properties of phenolic compounds, but nowadays this assumption is unlikely to explain their putative health effects, or at least to be the only explanation for them. New hypotheses about possible mechanisms have been postulated, including the influence of the interaction of polyphenols and gut microbiota and also the possibility that flavonoids or their metabolites could modify gene expression or act as potential modulators of intracellular signaling cascades. This paper reviews all these topics, from the classical view as antioxidants in the context of the Oxidative Stress theory to the most recent tendencies related with the modulation of redox signaling pathways, modification of gene expression or interactions with the intestinal microbiota. The use of C. elegans as a model organism for the study of the molecular mechanisms involved in biological activity of flavonoids is also discussed.

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