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Life Sciences Sep 2023Heart failure typically occurs early in the clinical course of sustained cardiac hypertrophy that is accompanied by maladaptive remodeling of the heart. It is critical...
Heart failure typically occurs early in the clinical course of sustained cardiac hypertrophy that is accompanied by maladaptive remodeling of the heart. It is critical to discover new mechanisms and effective therapeutic targets to prevent and cure pathological cardiac hypertrophy. The objective of the study was to evaluate the effects of circRNAs on NSD2-induced ventricular remodeling. We screened the dysregulated circRNAs in normal or NSD2 C57BL/6 mice with or without transverse aortic constriction (TAC), and found that circCmss1 significantly increased in normal TAC mice, but decreased in NSD2 TAC mice. Angiotensin II(Ang II)induced neonatal cardiomyocyte hypertrophy in vitro and the pressure overload-induced cardiac hypertrophy in vivo can be reduced by Knocking down circCmss1. We further investigated the downstream signaling of circCmss1 in the progression of NSD2-promoted ventricular remodeling and discovered that circCmss1 could interact with a transcription factor EIF4A3 and induce the expression of transferrin receptor 1 (TfR1), thus activating the ferroptosis in cardiomyocytes. This study highlights the significance of NSD2 activation of circCmss1/EIF4A3/TfR1 as therapeutic targets for treating pathological myocardial hypertrophy.
Topics: Animals; Mice; Cardiomegaly; Ferroptosis; Mice, Inbred C57BL; Myocytes, Cardiac; RNA, Circular; Ventricular Remodeling
PubMed: 37352916
DOI: 10.1016/j.lfs.2023.121873 -
Heart Failure Reviews Nov 2023Cardiovascular disease (CVD) has reached epidemic proportions and is a leading cause of death worldwide. One of the long-standing goals of scientists is to repair heart... (Review)
Review
Cardiovascular disease (CVD) has reached epidemic proportions and is a leading cause of death worldwide. One of the long-standing goals of scientists is to repair heart tissue damaged by various forms of CVD such as cardiac hypertrophy, dilated cardiomyopathy, myocardial infarction, heart fibrosis, and genetic and developmental heart defects such as heart valve deformities. Damaged or defective heart tissue has limited regenerative capacity and results in a loss of functioning myocardium. Advances in transcriptomic profiling technology have revealed that long noncoding RNA (lncRNA) is transcribed from what was once considered "junk DNA." It has since been discovered that lncRNAs play a critical role in the pathogenesis of various CVDs and in myocardial regeneration. This review will explore how lncRNAs impact various forms of CVD as well as those involved in cardiomyocyte regeneration. Further, we discuss the potential of lncRNAs as a therapeutic modality for treating CVD.
Topics: Humans; Cardiovascular Diseases; RNA, Long Noncoding; Myocardium; Cardiomegaly; Myocytes, Cardiac
PubMed: 37796408
DOI: 10.1007/s10741-023-10342-1 -
Journal of Strength and Conditioning... Oct 2023Nakao, S, Ikezoe, T, Taniguchi, M, Motomura, Y, Hirono, T, Nojiri, S, Hayashi, R, Tanaka, H, and Ichihashi, N. Effects of low-intensity torque-matched isometric training... (Randomized Controlled Trial)
Randomized Controlled Trial
Effects of Low-Intensity Torque-Matched Isometric Training at Long and Short Muscle Lengths of the Hamstrings on Muscle Strength and Hypertrophy: A Randomized Controlled Study.
Nakao, S, Ikezoe, T, Taniguchi, M, Motomura, Y, Hirono, T, Nojiri, S, Hayashi, R, Tanaka, H, and Ichihashi, N. Effects of low-intensity torque-matched isometric training at long and short muscle lengths of the hamstrings on muscle strength and hypertrophy: A randomized controlled study. J Strength Cond Res 37(10): 1978-1984, 2023-This study investigated the effects of low-intensity torque-matched isometric training on muscle hypertrophy and strengthening at long (LL) and short muscle lengths (SL). Twenty-eight young subjects completed an 8-week hamstring isometric training program (30% of maximal voluntary contraction (MVC) × 5 s × 20 repetitions × 5 sets × 3 times/week) at 30° knee flexion (LL) or 90° knee flexion (SL). The cross-sectional area (CSA) of the hamstrings and MVC were measured before and after the intervention. The active torque because of muscle contraction was calculated by subtracting the passive torque at rest from the total torque (30% MVC). The active torque was significantly lower in the LL training group than in the SL training group (p < 0.01), whereas there was no between-group difference in total torque during training. For CSA and MVC at 30° knee flexion, the split-plot analysis of variance (ANOVA) showed no significant time × group interaction; however, it did show a significant main effect of time (p < 0.05), indicating a significant increase after training intervention. As for MVC at 90° knee flexion, there was a significant time × group interaction (p < 0.05) and a significant simple main effect of time in both the LL (p < 0.01; Cohen's d effect size [ES] = 0.36) and SL (p < 0.01; ES = 0.64) training groups. Therefore, low-intensity isometric training at LL can induce hypertrophy and strengthening, even in cases where the active torque production is lower than that at SL, whereas the training at SL may be more effective for muscle strengthening at SL.
Topics: Humans; Torque; Muscle Strength; Hamstring Muscles; Hypertrophy; Muscles
PubMed: 37729512
DOI: 10.1519/JSC.0000000000004510 -
EBioMedicine Dec 2023Therapies are urgently required to ameliorate pathological cardiac hypertrophy and enhance cardiac function in heart failure. Our preliminary experiments have...
BACKGROUND
Therapies are urgently required to ameliorate pathological cardiac hypertrophy and enhance cardiac function in heart failure. Our preliminary experiments have demonstrated that exogenous NADPH exhibits a positive inotropic effect on isolated heart. This study aims to investigate the positive inotropic effects of NADPH in pathological cardiac hypertrophy and heart failure, as well as the underlying mechanisms involved.
METHODS
Endogenous plasma NADPH contents were determined in patients with chronic heart failure and control adults. The positive inotropic effects of NADPH were investigated in isolated toad heart or rat heart. The effects of NADPH were investigated in isoproterenol (ISO)-induced cardiac hypertrophy or transverse aortic constriction (TAC)-induced heart failure. The underlying mechanisms of NADPH were studied using SIRT3 knockout mice, echocardiography, Western blotting, transmission electron microscopy, and immunoprecipitation.
FINDINGS
The endogenous NADPH content in the blood of patients and animals with pathological cardiac hypertrophy or heart failure was significantly reduced compared with age-sex matched control subjects. Exogenous NADPH showed positive inotropic effects on the isolated normal and failing hearts, while antagonism of ATP receptor partially abolished the positive inotropic effect of NADPH. Exogenous NADPH administration significantly reduced heart weight indices, and improved cardiac function in the mice with pathological cardiac hypertrophy or heart failure. NADPH increased SIRT3 expression and activity, deacetylated target proteins, improved mitochondrial function and facilitated ATP production in the hypertrophic myocardium. Importantly, inhibition of SIRT3 abolished the positive inotropic effect of NADPH, and the anti-heart failure effect of NADPH was significantly reduced in the SIRT3 Knockout mice.
INTERPRETATION
Exogenous NADPH shows positive inotropic effect and improves energy metabolism via SIRT3 in pathological cardiac hypertrophy and heart failure. NADPH thus may be one of the potential candidates for the treatment of pathological cardiac hypertrophy or heart failure.
FUNDING
This work was supported by grants from the National Natural Science Foundation of China (No. 81973315, 82173811, 81730092), Natural Science Foundation of Jiangsu Higher Education (20KJA310008), Jiangsu Key Laboratory of Neuropsychiatric Diseases (BM2013003) and the Priority Academic Program Development of the Jiangsu Higher Education Institutes (PAPD).
Topics: Adult; Animals; Humans; Mice; Rats; Cardiomegaly; Energy Metabolism; Heart Failure; Mice, Knockout; Myocytes, Cardiac; NADP; Sirtuin 3; Cardiotonic Agents
PubMed: 37950995
DOI: 10.1016/j.ebiom.2023.104863 -
Circulation Research Jan 2024Cardiac hypertrophy is an intermediate stage in the development of heart failure. The structural and functional processes occurring in cardiac hypertrophy include...
BACKGROUND
Cardiac hypertrophy is an intermediate stage in the development of heart failure. The structural and functional processes occurring in cardiac hypertrophy include extensive gene reprogramming, which is dependent on epigenetic regulation and chromatin remodeling. However, the chromatin remodelers and their regulatory functions involved in the pathogenesis of cardiac hypertrophy are not well characterized.
METHODS
Protein interaction was determined by immunoprecipitation assay in primary cardiomyocytes and mouse cardiac samples subjected or not to transverse aortic constriction for 1 week. Chromatin immunoprecipitation and DNA sequencing (ChIP-seq) experiments were performed on the chromatin of adult mouse cardiomyocytes.
RESULTS
We report that the calcium-activated protein phosphatase CaN (calcineurin), its endogenous inhibitory protein carabin, the STK24 (STE20-like protein kinase 3), and the histone monomethyltransferase, MLL3 (mixed lineage leukemia 3) form altogether a macromolecular complex at the chromatin of cardiomyocytes. Under basal conditions, carabin prevents CaN activation while the serine/threonine kinase STK24 maintains MLL3 inactive via phosphorylation. After 1 week of transverse aortic constriction, both carabin and STK24 are released from the CaN-MLL3 complex leading to the activation of CaN, dephosphorylation of MLL3, and in turn, histone H3 lysine 4 monomethylation. Selective cardiac MLL3 knockdown mitigates hypertrophy, and chromatin immunoprecipitation and DNA sequencing analysis demonstrates that MLL3 is de novo recruited at the transcriptional start site of genes implicated in cardiomyopathy in stress conditions. We also show that CaN and MLL3 colocalize at chromatin and that CaN activates MLL3 histone methyl transferase activity at distal intergenic regions under hypertrophic conditions.
CONCLUSIONS
Our study reveals an unsuspected epigenetic mechanism of CaN that directly regulates MLL3 histone methyl transferase activity to promote cardiac remodeling.
Topics: Animals; Mice; Calcineurin; Cardiomegaly; Chromatin; Epigenesis, Genetic; Histones; Myocytes, Cardiac; Transferases; Ventricular Remodeling
PubMed: 38084599
DOI: 10.1161/CIRCRESAHA.123.323458 -
Journal of the American Heart... Feb 2024Alveolar hypoxia is protective in the context of cardiovascular and ischemic heart disease; however, the underlying mechanisms are incompletely understood. The present...
BACKGROUND
Alveolar hypoxia is protective in the context of cardiovascular and ischemic heart disease; however, the underlying mechanisms are incompletely understood. The present study sought to test the hypothesis that hypoxia is cardioprotective in left ventricular pressure overload (LVPO)-induced heart failure. We furthermore aimed to test that overlapping mechanisms promote cardiac recovery in heart failure patients following left ventricular assist device-mediated mechanical unloading and circulatory support.
METHODS AND RESULTS
We established a novel murine model of combined chronic alveolar hypoxia and LVPO following transverse aortic constriction (HxTAC). The HxTAC model is resistant to cardiac hypertrophy and the development of heart failure. The cardioprotective mechanisms identified in our HxTAC model include increased activation of HIF (hypoxia-inducible factor)-1α-mediated angiogenesis, attenuated induction of genes associated with pathological remodeling, and preserved metabolic gene expression as identified by RNA sequencing. Furthermore, LVPO decreased and increased mRNA expression under normoxic conditions, which was attenuated under hypoxic conditions and may induce additional hypoxia-mediated cardioprotective effects. Analysis of samples from patients with advanced heart failure that demonstrated left ventricular assist device-mediated myocardial recovery revealed a similar expression pattern for and as observed in HxTAC hearts.
CONCLUSIONS
Hypoxia attenuates LVPO-induced heart failure. Cardioprotective pathways identified in the HxTAC model might also contribute to cardiac recovery following left ventricular assist device support. These data highlight the potential of our novel HxTAC model to identify hypoxia-mediated cardioprotective mechanisms and therapeutic targets that attenuate LVPO-induced heart failure and mediate cardiac recovery following mechanical circulatory support.
Topics: Humans; Mice; Animals; Heart Failure; Cardiomegaly; Myocardium; Aortic Valve Stenosis; Hypoxia; Ventricular Remodeling; Disease Models, Animal
PubMed: 38293923
DOI: 10.1161/JAHA.123.033553 -
Physiological Research Aug 2023G protein-coupled receptor 81 (GPR81), a selective receptor for lactate, expresses in skeletal muscle cells, but the physiological role of GPR81 in skeletal muscle has...
G protein-coupled receptor 81 (GPR81), a selective receptor for lactate, expresses in skeletal muscle cells, but the physiological role of GPR81 in skeletal muscle has not been fully elucidated. As it has been reported that the lactate administration induces muscle hypertrophy, the stimulation of GPR81 has been suggested to mediate muscle hypertrophy. To clarify the contribution of GPR81 activation in skeletal muscle hypertrophy, in the present study, we investigated the effect of GPR81 agonist administration on skeletal muscle mass in mice. Male C57BL/6J mice were randomly divided into control group and GPR81 agonist-administered group that received oral administration of the specific GPR81 agonist 3-Chloro-5-hydroxybenzoic acid (CHBA). In both fast-twitch plantaris and slow-twitch soleus muscles of mice, the protein expression of GPR81 was observed. Oral administration of CHBA to mice significantly increased absolute muscle weight and muscle weight relative to body weight in the two muscles. Moreover, both absolute and relative muscle protein content in the two muscles were significantly increased by CHBA administration. CHBA administration also significantly upregulated the phosphorylation level of p42/44 extracellular signal-regulated kinase-1/2 (ERK1/2) and p90 ribosomal S6 kinase (p90RSK). These observations suggest that activation of GRP81 stimulates increased the mass of two types of skeletal muscle in mice in vivo. Lactate receptor GPR81 may positively affect skeletal muscle mass through activation of ERK pathway.
Topics: Mice; Male; Animals; Lactic Acid; Mice, Inbred C57BL; Muscle, Skeletal; Muscle Fibers, Skeletal; Receptors, G-Protein-Coupled; Hypertrophy
PubMed: 37795889
DOI: 10.33549/physiolres.935004 -
The Journal of Clinical Investigation May 2024One of the features of pathological cardiac hypertrophy is enhanced translation and protein synthesis. Translational inhibition has been shown to be an effective means...
One of the features of pathological cardiac hypertrophy is enhanced translation and protein synthesis. Translational inhibition has been shown to be an effective means of treating cardiac hypertrophy, although system-wide side effects are common. Regulators of translation, such as cardiac-specific long noncoding RNAs (lncRNAs), could provide new, more targeted therapeutic approaches to inhibit cardiac hypertrophy. Therefore, we generated mice lacking a previously identified lncRNA named CARDINAL to examine its cardiac function. We demonstrate that CARDINAL is a cardiac-specific, ribosome-associated lncRNA and show that its expression was induced in the heart upon pathological cardiac hypertrophy and that its deletion in mice exacerbated stress-induced cardiac hypertrophy and augmented protein translation. In contrast, overexpression of CARDINAL attenuated cardiac hypertrophy in vivo and in vitro and suppressed hypertrophy-induced protein translation. Mechanistically, CARDINAL interacted with developmentally regulated GTP-binding protein 1 (DRG1) and blocked its interaction with DRG family regulatory protein 1 (DFRP1); as a result, DRG1 was downregulated, thereby modulating the rate of protein translation in the heart in response to stress. This study provides evidence for the therapeutic potential of targeting cardiac-specific lncRNAs to suppress disease-induced translational changes and to treat cardiac hypertrophy and heart failure.
Topics: Animals; RNA, Long Noncoding; Mice; Cardiomegaly; Protein Biosynthesis; Humans; Mice, Knockout; GTP-Binding Proteins; Myocytes, Cardiac
PubMed: 38743498
DOI: 10.1172/JCI169112 -
American Journal of Physiology.... Dec 2023Muscle mass is balanced between hypertrophy and atrophy by cellular processes, including activation of the protein kinase B-mechanistic target of rapamycin (Akt-mTOR)...
Muscle mass is balanced between hypertrophy and atrophy by cellular processes, including activation of the protein kinase B-mechanistic target of rapamycin (Akt-mTOR) signaling cascade. Stressors apart from exercise and nutrition, such as heat stress, can stimulate the heat shock protein A (HSPA) and C (HSPC) families alongside hypertrophic signaling factors and muscle growth. The effects of heat stress on HSP expression and Akt-mTOR activation in human skeletal muscle and their magnitude of activation compared with known hypertrophic stimuli are unclear. Here, we show a single session of whole body heat stress following resistance exercise increases the expression of HSPA and activation of the Akt-mTOR cascade in skeletal muscle compared with resistance exercise in a healthy, resistance-trained population. Heat stress alone may also exert similar effects, though the responses are notably variable and require further investigation. In addition, acute heat stress in C2C12 muscle cells enhanced myotube growth and myogenic fusion, albeit to a lesser degree than growth factor-mediated hypertrophy. Though the mechanisms by which heat stress stimulates hypertrophy-related signaling and the potential mechanistic role of HSPs remain unclear, these findings provide additional evidence implicating heat stress as a novel growth stimulus when combined with resistance exercise in human skeletal muscle and alone in isolated murine muscle cells. We believe these findings will help drive further applied and mechanistic investigation into how heat stress influences muscular hypertrophy and atrophy. We show that acute resistance exercise followed by whole body heat stress increases the expression of HSPA and increases activation of the Akt-mTOR cascade in a physically active and resistance-trained population.
Topics: Humans; Mice; Animals; Proto-Oncogene Proteins c-akt; Heat-Shock Proteins; Muscle, Skeletal; Heat-Shock Response; Heat Stress Disorders; Hypertrophy; TOR Serine-Threonine Kinases; Atrophy
PubMed: 37842742
DOI: 10.1152/ajpregu.00031.2023 -
Toxicology and Applied Pharmacology Aug 2023Pristimerin (PM), serving as a biological component mainly obtained from Celastraceae and Hippocrateaceae families, has been extensively explored for its numerous...
Pristimerin (PM), serving as a biological component mainly obtained from Celastraceae and Hippocrateaceae families, has been extensively explored for its numerous pharmacological activities, especially anti-cancer activity. However, the function of PM on pathological cardiac hypertrophy is poorly understood. This work was intended to investigate the effects of PM on pressure-overload induced myocardial hypertrophy and its potential pathways. Mouse model of pathological cardiac hypertrophy was generated by transverse aortic constriction (TAC) or minipump administration of the β-adrenergic agonist ISO for 4 weeks, and PM (0.5 mg/Kg/d, i.p.) was treated for 2 weeks. PPARα-/- mice received TAC surgery were used for mechanism exploration. Moreover, neonatal rat cardiomyocytes (NRCMs) were utilized to explore the effect of PM following Angiotensin II (Ang II, 1.0 μM) administration. We found that PM attenuated pressure-overload induced cardiac dysfunction, myocardial hypertrophy and fibrosis in mice. Likewise, PM incubation dramatically reversed Ang II-mediated cardiomyocytes hypertrophy in NRCMs. RNA-Sequence showed that PM selectively contributed to improvement of PPARα/PGC1 signaling, while silencing PPARα abrogated the beneficial effects of PM on Ang II-treated NRCMs. Importantly, PM ameliorated Ang II-induced mitochondrial dysfunction and decrease in metabolic genes, whereas knockdown of PPARα eliminated these alterations in NRCMs. Similarly, PM presented limited protective effects on pressure-overload induced systolic dysfunction and myocardial hypertrophy in PPARα deficient mice. Overall, this study revealed that PM exerted protective activity against pathological cardiac hypertrophy through improvement of PPARα/PGC1 pathway.
Topics: Rats; Mice; Animals; PPAR alpha; Cardiomegaly; Myocytes, Cardiac; Signal Transduction; Mice, Inbred C57BL; Angiotensin II
PubMed: 37269933
DOI: 10.1016/j.taap.2023.116572