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Cardiovascular Research Dec 2023Regular exercise training benefits cardiovascular health and effectively reduces the risk for cardiovascular disease. Circular RNAs (circRNAs) play important roles in...
AIMS
Regular exercise training benefits cardiovascular health and effectively reduces the risk for cardiovascular disease. Circular RNAs (circRNAs) play important roles in cardiac pathophysiology. However, the role of circRNAs in response to exercise training and biological mechanisms responsible for exercise-induced cardiac protection remain largely unknown.
METHODS AND RESULTS
RNA sequencing was used to profile circRNA expression in adult mouse cardiomyocytes that were isolated from mice with or without exercise training. Exercise-induced circRNA circUtrn was significantly increased in swimming-trained adult mouse cardiomyocytes. In vivo, circUtrn was found to be required for exercise-induced physiological cardiac hypertrophy. circUtrn inhibition abolished the protective effects of exercise on myocardial ischaemia-reperfusion remodelling. circUtrn overexpression prevented myocardial ischaemia-reperfusion-induced acute injury and pathological cardiac remodelling. In vitro, overexpression of circUtrn promoted H9 human embryonic stem cell-induced cardiomyocyte growth and survival via protein phosphatase 5 (PP5). Mechanistically, circUtrn directly bound to PP5 and regulated the stability of PP5 in a ubiquitin-proteasome-dependent manner. Hypoxia-inducible factor 1α-dependent splicing factor SF3B1 acted as an upstream regulator of circUtrn in cardiomyocytes.
CONCLUSION
The circRNA circUtrn is upregulated upon exercise training in the heart. Overexpression of circUtrn can prevent myocardial I/R-induced injury and pathological cardiac remodelling.
Topics: Animals; Humans; Mice; Cardiomegaly; Exercise; Myocardial Reperfusion Injury; Myocytes, Cardiac; RNA, Circular; Ventricular Remodeling; Utrophin
PubMed: 37897547
DOI: 10.1093/cvr/cvad161 -
Cells Nov 2023Satellite cells (SCs) are adult muscle stem cells that are mobilized when muscle homeostasis is perturbed. Here we show that RhoA in SCs is indispensable to have correct...
Satellite cells (SCs) are adult muscle stem cells that are mobilized when muscle homeostasis is perturbed. Here we show that RhoA in SCs is indispensable to have correct muscle regeneration and hypertrophy. In particular, the absence of RhoA in SCs prevents a correct SC fusion both to other RhoA-deleted SCs (regeneration context) and to growing control myofibers (hypertrophy context). We demonstrated that RhoA is dispensable for SCs proliferation and differentiation; however, RhoA-deleted SCs have an inefficient movement even if their cytoskeleton assembly is not altered. Proliferative myoblast and differentiated myotubes without RhoA display a decreased expression of , suggesting a crosstalk between these genes for myoblast fusion regulation. These findings demonstrate the importance of RhoA in SC fusion regulation and its requirement to achieve an efficient skeletal muscle homeostasis restoration.
Topics: Humans; Cell Communication; Hypertrophy; Muscle Fibers, Skeletal; Satellite Cells, Skeletal Muscle; Cell Fusion; rhoA GTP-Binding Protein
PubMed: 38067102
DOI: 10.3390/cells12232673 -
Cardiovascular Diabetology Jul 2023L-type Ca channel Ca1.2 is essential for cardiomyocyte excitation, contraction and gene transcription in the heart, and abnormal functions of cardiac Ca1.2 channels are...
BACKGROUND
L-type Ca channel Ca1.2 is essential for cardiomyocyte excitation, contraction and gene transcription in the heart, and abnormal functions of cardiac Ca1.2 channels are presented in diabetic cardiomyopathy. However, the underlying mechanisms are largely unclear. The functions of Ca1.2 channels are subtly modulated by splicing factor-mediated alternative splicing (AS), but whether and how Ca1.2 channels are alternatively spliced in diabetic heart remains unknown.
METHODS
Diabetic rat models were established by using high-fat diet in combination with low dose streptozotocin. Cardiac function and morphology were assessed by echocardiography and HE staining, respectively. Isolated neonatal rat ventricular myocytes (NRVMs) were used as a cell-based model. Cardiac Ca1.2 channel functions were measured by whole-cell patch clamp, and intracellular Ca concentration was monitored by using Fluo-4 AM.
RESULTS
We find that diabetic rats develop diastolic dysfunction and cardiac hypertrophy accompanied by an increased Ca1.2 channel with alternative exon 9* (Ca1.2), but unchanged that with alternative exon 8/8a or exon 33. The splicing factor Rbfox2 expression is also increased in diabetic heart, presumably because of dominate-negative (DN) isoform. Unexpectedly, high glucose cannot induce the aberrant expressions of Ca1.2 exon 9* and Rbfox2. But glycated serum (GS), the mimic of advanced glycation end-products (AGEs), upregulates Ca1.2 channels proportion and downregulates Rbfox2 expression in NRVMs. By whole-cell patch clamp, we find GS application hyperpolarizes the current-voltage curve and window currents of cardiac Ca1.2 channels. Moreover, GS treatment raises K-triggered intracellular Ca concentration ([Ca]), enlarges cell surface area of NRVMs and induces hypertrophic genes transcription. Consistently, siRNA-mediated knockdown of Rbfox2 in NRVMs upregulates Ca1.2 channel, shifts Ca1.2 window currents to hyperpolarization, increases [Ca] and induces cardiomyocyte hypertrophy.
CONCLUSIONS
AGEs, not glucose, dysregulates Rbfox2 which thereby increases Ca1.2 channels and hyperpolarizes channel window currents. These make the channels open at greater negative potentials and lead to increased [Ca] in cardiomyocytes, and finally induce cardiomyocyte hypertrophy in diabetes. Our work elucidates the underlying mechanisms for Ca1.2 channel regulation in diabetic heart, and targeting Rbfox2 to reset the aberrantly spliced Ca1.2 channel might be a promising therapeutic approach in diabetes-induced cardiac hypertrophy.
Topics: Animals; Rats; Calcium; Calcium Channels, L-Type; Cardiomegaly; Diabetes Mellitus, Experimental; Glycation End Products, Advanced; Myocytes, Cardiac; RNA Splicing Factors
PubMed: 37415128
DOI: 10.1186/s12933-023-01894-5 -
Cardiovascular Diabetology Mar 2024Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective antidiabetic drugs with potential cardiovascular benefits. Despite their well-established role in... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective antidiabetic drugs with potential cardiovascular benefits. Despite their well-established role in reducing the risk of major adverse cardiovascular events (MACE), their impact on heart failure (HF) remains unclear. Therefore, our study examined the cardioprotective effects of tirzepatide (TZT), a novel glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptor agonist.
METHODS
A three-steps approach was designed: (i) Meta-analysis investigation with the primary objective of assessing major adverse cardiovascular events (MACE) occurrence from major randomized clinical trials.; (ii) TZT effects on a human cardiac AC16 cell line exposed to normal (5 mM) and high (33 mM) glucose concentrations for 7 days. The gene expression and protein levels of primary markers related to cardiac fibrosis, hypertrophy, and calcium modulation were evaluated. (iii) In silico data from bioinformatic analyses for generating an interaction map that delineates the potential mechanism of action of TZT.
RESULTS
Meta-analysis showed a reduced risk for MACE events by TZT therapy (HR was 0.59 (95% CI 0.40-0.79, Heterogeneity: r = 0.01, I = 23.45%, H = 1.31). In the human AC16 cardiac cell line treatment with 100 nM TZT contrasted high glucose (HG) levels increase in the expression of markers associated with fibrosis, hypertrophy, and cell death (p < 0.05 for all investigated markers). Bioinformatics analysis confirmed the interaction between the analyzed markers and the associated pathways found in AC16 cells by which TZT affects apoptosis, fibrosis, and contractility, thus reducing the risk of heart failure.
CONCLUSION
Our findings indicate that TZT has beneficial effects on cardiac cells by positively modulating cardiomyocyte death, fibrosis, and hypertrophy in the presence of high glucose concentrations. This suggests that TZT may reduce the risk of diabetes-related cardiac damage, highlighting its potential as a therapeutic option for heart failure management clinical trials. Our study strongly supports the rationale behind the clinical trials currently underway, the results of which will be further investigated to gain insights into the cardiovascular safety and efficacy of TZT.
Topics: Humans; Heart Failure; Diabetes Mellitus; Hypertrophy; Hypoglycemic Agents; Myocytes, Cardiac; Fibrosis; Glucose; Glucagon-Like Peptide-1 Receptor; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-2 Receptor; Gastric Inhibitory Polypeptide
PubMed: 38555463
DOI: 10.1186/s12933-024-02203-4 -
International Journal of Molecular... Feb 2024Mitochondrial dysfunction, a feature of heart failure, leads to a progressive decline in bioenergetic reserve capacity, consisting in a shift of energy production from... (Review)
Review
Mitochondrial dysfunction, a feature of heart failure, leads to a progressive decline in bioenergetic reserve capacity, consisting in a shift of energy production from mitochondrial fatty acid oxidation to glycolytic pathways. This adaptive process of cardiomyocytes does not represent an effective strategy to increase the energy supply and to restore the energy homeostasis in heart failure, thus contributing to a vicious circle and to disease progression. The increased oxidative stress causes cardiomyocyte apoptosis, dysregulation of calcium homeostasis, damage of proteins and lipids, leakage of mitochondrial DNA, and inflammatory responses, finally stimulating different signaling pathways which lead to cardiac remodeling and failure. Furthermore, the parallel neurohormonal dysregulation with angiotensin II, endothelin-1, and sympatho-adrenergic overactivation, which occurs in heart failure, stimulates ventricular cardiomyocyte hypertrophy and aggravates the cellular damage. In this review, we will discuss the pathophysiological mechanisms related to mitochondrial dysfunction, which are mainly dependent on increased oxidative stress and perturbation of the dynamics of membrane potential and are associated with heart failure development and progression. We will also provide an overview of the potential implication of mitochondria as an attractive therapeutic target in the management and recovery process in heart failure.
Topics: Humans; Mitochondria, Heart; Heart Failure; Cardiomegaly; Myocytes, Cardiac; Oxidative Stress; Mitochondrial Diseases
PubMed: 38473911
DOI: 10.3390/ijms25052667 -
Sports Medicine (Auckland, N.Z.) Feb 2024Many sports require maximal strength and endurance performance. Concurrent strength and endurance training can lead to suboptimal training adaptations. However, how... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Many sports require maximal strength and endurance performance. Concurrent strength and endurance training can lead to suboptimal training adaptations. However, how adaptations differ between males and females is currently unknown. Additionally, current training status may affect training adaptations.
OBJECTIVE
We aimed to assess sex-specific differences in adaptations in strength, power, muscle hypertrophy, and maximal oxygen consumption ( O) to concurrent strength and endurance training in healthy adults. Second, we investigated how training adaptations are influenced by strength and endurance training status.
METHODS
A systematic review and meta-analysis was conducted according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, and a Cochrane risk of bias was evaluated. ISI Web of science, PubMed/MEDLINE, and SPORTDiscus databases were searched using the following inclusion criteria: healthy adults aged 18-50 years, intervention period of ≥ 4 weeks, and outcome measures were defined as upper- and lower-body strength, power, hypertrophy, and/or O. A meta-analysis was performed using a random-effects model and reported in standardized mean differences.
RESULTS
In total, 59 studies with 1346 participants were included. Concurrent training showed blunted lower-body strength adaptations in males, but not in females (male: - 0.43, 95% confidence interval [- 0.64 to - 0.22], female: 0.08 [- 0.34 to 0.49], group difference: P = 0.03). No sex differences were observed for changes in upper-body strength (P = 0.67), power (P = 0.37), or O (P = 0.13). Data on muscle hypertrophy were insufficient to draw any conclusions. For training status, untrained but not trained or highly trained endurance athletes displayed lower O gains with concurrent training (P = 0.04). For other outcomes, no differences were found between untrained and trained individuals, both for strength and endurance training status.
CONCLUSIONS
Concurrent training results in small interference for lower-body strength adaptations in males, but not in females. Untrained, but not trained or highly trained endurance athletes demonstrated impaired improvements in O following concurrent training. More studies on females and highly strength-trained and endurance-trained athletes are warranted.
CLINICAL TRIAL REGISTRATION
PROSPERO: CRD42022370894.
Topics: Adult; Humans; Male; Female; Endurance Training; Physical Endurance; Athletes; Sports; Hypertrophy; Muscle Strength; Resistance Training
PubMed: 37847373
DOI: 10.1007/s40279-023-01943-9 -
Hypertension (Dallas, Tex. : 1979) Dec 2023Cardiac hypertrophy and subsequent heart failure impose a considerable burden on public health worldwide. Impaired protein degradation, especially endo-lysosome-mediated...
BACKGROUND
Cardiac hypertrophy and subsequent heart failure impose a considerable burden on public health worldwide. Impaired protein degradation, especially endo-lysosome-mediated degradation of membrane proteins, is associated with cardiac hypertrophy progression. CHMP4C (charged multivesicular body protein 4C), a critical constituent of multivesicular bodies, is involved in cellular trafficking and signaling. However, the specific role of CHMP4C in the progression of cardiac hypertrophy remains largely unknown.
METHODS
Mouse models with CHMP4C knockout or cardiadc-specific overexpression were subjected to transverse aortic constriction surgery for 4 weeks. Cardiac morphology and function were assessed through histological staining and echocardiography. Confocal imaging and coimmunoprecipitation assays were performed to identify the direct target of CHMP4C. An EGFR (epidermal growth factor receptor) inhibitor was administrated to determine whether effects of CHMP4C on cardiac hypertrophy were EGFR dependent.
RESULTS
CHMP4C was significantly upregulated in both pressure-overloaded mice and spontaneously hypertensive rats. Compared with wild-type mice, CHMP4C deficiency exacerbated transverse aortic constriction-induced cardiac hypertrophy, whereas CHMP4C overexpression in cardiomyocytes attenuated cardiac dysfunction. Mechanistically, the effect of CHMP4C on cardiac hypertrophy relied on the EGFR signaling pathway. Fluorescent staining and coimmunoprecipitation assays confirmed that CHMP4C interacts directly with EGFR and promotes lysosome-mediated degradation of activated EGFR, thus attenuating cardiac hypertrophy. Notably, an EGFR inhibitor canertinib counteracted the exacerbation of cardiac hypertrophy induced by CHMP4C knockdown in vitro and in vivo.
CONCLUSIONS
CHMP4C represses cardiac hypertrophy by modulating lysosomal degradation of EGFR and is a potential therapeutic candidate for cardiac hypertrophy.
Topics: Rats; Mice; Animals; Endosomal Sorting Complexes Required for Transport; Cardiomegaly; Heart Failure; ErbB Receptors; Myocytes, Cardiac; Lysosomes; Mice, Knockout; Mice, Inbred C57BL; Disease Models, Animal
PubMed: 37846580
DOI: 10.1161/HYPERTENSIONAHA.123.21427 -
British Journal of Pharmacology Nov 2023Pathological cardiomyocyte hypertrophy is a response to cardiac stress that typically leads to heart failure. Despite being a primary contributor to pathological cardiac...
BACKGROUND AND PURPOSE
Pathological cardiomyocyte hypertrophy is a response to cardiac stress that typically leads to heart failure. Despite being a primary contributor to pathological cardiac remodelling, the therapeutic space that targets hypertrophy is limited. Here, we apply a network model to virtually screen for FDA-approved drugs that induce or suppress cardiomyocyte hypertrophy.
EXPERIMENTAL APPROACH
A logic-based differential equation model of cardiomyocyte signalling was used to predict drugs that modulate hypertrophy. These predictions were validated against curated experiments from the prior literature. The actions of midostaurin were validated in new experiments using TGFβ- and noradrenaline (NE)-induced hypertrophy in neonatal rat cardiomyocytes.
KEY RESULTS
Model predictions were validated in 60 out of 70 independent experiments from the literature and identify 38 inhibitors of hypertrophy. We additionally predict that the efficacy of drugs that inhibit cardiomyocyte hypertrophy is often context dependent. We predicted that midostaurin inhibits cardiomyocyte hypertrophy induced by TGFβ, but not noradrenaline, exhibiting context dependence. We further validated this prediction by cellular experiments. Network analysis predicted critical roles for the PI3K and RAS pathways in the activity of celecoxib and midostaurin, respectively. We further investigated the polypharmacology and combinatorial pharmacology of drugs. Brigatinib and irbesartan in combination were predicted to synergistically inhibit cardiomyocyte hypertrophy.
CONCLUSION AND IMPLICATIONS
This study provides a well-validated platform for investigating the efficacy of drugs on cardiomyocyte hypertrophy and identifies midostaurin for consideration as an antihypertrophic drug.
Topics: Rats; Animals; Myocytes, Cardiac; Cardiomegaly; Signal Transduction; Heart Failure; Transforming Growth Factor beta; Cells, Cultured
PubMed: 37302817
DOI: 10.1111/bph.16163 -
Archives of Biochemistry and Biophysics Oct 2023Maladaptive right ventricular (RV) remodeling is the most important pathological feature of pulmonary hypertension (PH), involving processes such as myocardial...
BACKGROUND
Maladaptive right ventricular (RV) remodeling is the most important pathological feature of pulmonary hypertension (PH), involving processes such as myocardial hypertrophy and fibrosis. A growing number of studies have shown that mitochondria-associated endoplasmic reticulum membranes (MAMs) are involved in various physiological and pathological processes, such as calcium homeostasis, lipid metabolism, inflammatory response, mitochondrial dynamics, and autophagy/mitophagy. The abnormal expression of MAMs-related factors is closely related to the occurrence and development of heart-related diseases. However, the role of MAM-related factors in the maladaptive RV remodeling of PH rats remains unclear.
METHODS AND RESULTS
We first obtained the transcriptome data of RV tissues from PH rats induced by Su5416 combined with hypoxia treatment (SuHx) from the Gene Expression Omnibus (GEO) database. The results showed that two MAMs-related genes (Opa1 and Mfn2) were significantly down-regulated in RV tissues of SuHx rats, accompanied by significant up-regulation of cardiac hypertrophy-related genes (such as Nppb and Myh7). Subsequently, using the SuHx-induced PH rat model, we found that the downregulation of mitochondrial fusion proteins Opa1 and Mfn2 may be involved in maladaptive RV remodeling by accelerating mitochondrial dysfunction. Finally, at the cellular level, we found that overexpression of Opa1 and Mfn2 could inhibit hypoxia-induced mitochondrial fission and reduce ROS production in H9c2 cardiomyocytes, thereby retarded the progression of cardiomyocyte hypertrophy.
CONCLUSIONS
The down-regulation of mitochondrial fusion protein Opa1/Mfn2 can accelerate cardiomyocyte hypertrophy and then participate in maladaptive RV remodeling in SuHx-induced PH rats, which may be potential targets for preventing maladaptive RV remodeling.
Topics: Rats; Animals; Hypertension, Pulmonary; Myocytes, Cardiac; Mitochondrial Dynamics; Down-Regulation; Mitochondrial Proteins; Mitochondria; Hydrolases; Hypoxia; Hypertrophy; Ventricular Remodeling; GTP Phosphohydrolases
PubMed: 37696382
DOI: 10.1016/j.abb.2023.109743 -
Cellular Signalling Jan 2024Cardiac hypertrophy is studied in relation to energy metabolism, autophagy, and ferroptosis, which are associated with cardiovascular adverse events and chronic heart...
BACKGROUND
Cardiac hypertrophy is studied in relation to energy metabolism, autophagy, and ferroptosis, which are associated with cardiovascular adverse events and chronic heart failure. Protein kinase D (PKD) has been shown to play a degenerative role in cardiac hypertrophy. However, the role of ferroptosis in PKD-involved cardiac hypertrophy remains unclear.
METHODS
A cardiac hypertrophy model was induced by a subcutaneous injection of angiotensin II (Ang II) for 4 weeks. Adeno-associated virus serotype 9 (AAV9)-PKD or AAV9-Negative control were injected through the caudal vein 2 weeks prior to the injection of Ang II. The degree of cardiac hypertrophy was assessed using echocardiography and by observing cardiomyocyte morphology. Levels of ferroptosis and protein expression in the Jun N-terminal kinase (JNK)/P53 signaling pathway were measured both in vivo and in vitro.
RESULTS
The results indicated that PKD knockdown reduces Ang II-induced cardiac hypertrophy, enhances cardiac function and inhibits ferroptosis. The involvement of the JNK/P53 pathway in this process was further confirmed by in vivo and in vitro experiments.
CONCLUSION
In conclusion, our findings suggest that PKD knockdown mitigates Ang II-induced cardiac hypertrophy and ferroptosis via the JNK/P53 signaling pathway.
Topics: Humans; Angiotensin II; Tumor Suppressor Protein p53; Ferroptosis; Cardiomegaly; Myocytes, Cardiac; Signal Transduction
PubMed: 37972803
DOI: 10.1016/j.cellsig.2023.110974