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Pathological cardiac hypertrophy serves as a significant foundation for cardiac dysfunction and heart failure. Recently, growing evidence has revealed that microRNAs (miRNAs) play multiple roles in biological processes and participate in cardiovascular diseases. In the present research, we investigate the impact of miRNA-34c-5p on cardiac hypertrophy and the mechanism involved. The expression of miR-34c-5p was proved to be elevated in heart tissues from isoprenaline (ISO)-infused mice. ISO also promoted miR-34c-5p level in primary cultures of neonatal rat cardiomyocytes (NRCMs). Transfection with miR-34c-5p mimic enhanced cell surface area and expression levels of foetal-type genes atrial natriuretic factor (Anf) and β -myosin heavy chain (β-Mhc) in NRCMs. In contrast, treatment with miR-34c-5p inhibitor attenuated ISO-induced hypertrophic responses. Enforced expression of miR-34c-5p by tail intravenous injection of its agomir led to cardiac dysfunction and hypertrophy in mice, whereas inhibiting miR-34c-5p by specific antagomir could protect the animals against ISO-triggered hypertrophic abnormalities. Mechanistically, miR-34c-5p suppressed autophagic flux in cardiomyocytes, which contributed to the development of hypertrophy. Furthermore, the autophagy-related gene 4B (ATG4B) was identified as a direct target of miR-34c-5p, and miR-34c-5p was certified to interact with 3′ untranslated region of Atg4b mRNA by dual-luciferase reporter assay. miR-34c-5p reduced the expression of ATG4B, thereby resulting in decreased autophagy activity and induction of hypertrophy. Inhibition of miR-34c-5p abolished the detrimental effects of ISO by restoring ATG4B and increasing autophagy. In conclusion, our findings illuminate that miR-34c-5p participates in ISO-induced cardiac hypertrophy, at least partly through suppressing ATG4B and autophagy. It suggests that regulation of miR-34c-5p may offer a new way for handling hypertrophy-related cardiac dysfunction. Isoprenaline promotes miR-34c-5p expression in cardiomyocytes, which inhibits autophagy by targeting ATG4B. The miR-34c-5p/ATG4B axis might be an important pathway contributing to the development of cardiac hypertrophy. [Display omitted] [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) regulate multiple biological processes and participate in various cardiovascular diseases. This study aims to investigate the role of miR‐339‐5p in cardiomyocyte hypertrophy and the involved mechanism. Neonatal rat cardiomyocytes (NRCMs) were cultured and stimulated with isoproterenol (ISO). The hypertrophic responses were monitored by measuring the cell surface area and expression of hypertrophic markers including β‐myosin heavy chain (β‐MHC) and atrial natriuretic factor (ANF). Bioinformatic prediction tools and dual‐luciferase reporter assay were performed to identify the target gene of miR‐339‐5p. Quantitative real‐time polymerase chain reaction and western blot analysis were used to determine the levels of miR‐339‐5p and its downstream effectors. Our data showed that miR‐339‐5p was upregulated during cardiomyocyte hypertrophy triggered by ISO. MiR‐339‐5p overexpression resulted in enlargement of cell size and increased the levels of hypertrophic markers. In contrast, inhibition of miR‐339‐5p significantly attenuated ISO‐induced hypertrophic responses of NRCMs. Valosin‐containing protein (VCP), a suppressor of cardiac hypertrophy via inhibiting mechanistic target of rapamycin (mTOR) signaling, was validated as a target of miR‐339‐5p. MiR‐339‐5p suppressed VCP protein expression, leading to elevated phosphorylation of mTOR and ribosomal protein S6 kinase (S6K). VCP depletion activated the mTOR/S6K cascade and could compromise the anti‐hypertrophic effects of miR‐339‐5p inhibitor. Additionally, the hypertrophic responses caused by miR‐339‐5p was alleviated in the presence of mTOR inhibitor rapamycin. In conclusion, our research revealed that miR‐339‐5p promoted ISO‐induced cardiomyocyte hypertrophy by targeting VCP to activate the mTOR signaling, suggesting a promising therapeutic intervention by interfering miR‐339‐5p. [ABSTRACT FROM AUTHOR]

Aim: By activating prostacyclin receptors (IP receptors), prostacyclin (PGI2) exerts cardiovascular protective effects such as vasodilation and inhibition of vascular smooth muscle cell (VSMC) proliferation. However, IP receptors are dysfunctional under pathological conditions, and PGI2 produces detrimental effects that are opposite to its physiological protective effects via thromboxane‐prostanoid (TP) receptors. This attempted to investigate whether or not IP receptor dysfunction facilitates the shift of PGI2 action. Methods: The effects of PGI2 and its stable analog iloprost on VSMC phenotypic transformation and proliferation were examined in A10 cells silencing IP receptors, in human aortic VSMCs (HAVSMCs) knocked down IP receptor by CRISPR‐Cas9, or in HAVSMCs transfected with a dysfunctional mutation of IP receptor IPR212C. Results: PGI2/iloprost treatment stimulated cell proliferation, upregulated synthetic proteins and downregulated contractile proteins, suggesting that PGI2/iloprost promotes VSMC phenotypic transformation in IP‐deficient cells. The effect of PGI2/iloprost was prevented by TP antagonist S18886 or TP knockdown, indicating that the VSMC detrimental effect of PGI2 is dependent on TP receptor. RNA sequencing and Western blotting results showed that RhoA/ROCKs, MEK1/2 and JNK signalling cascades were involved. Moreover, IP deficiency increased the distribution of TP receptors at the cell membrane. Conclusion: PGI2 induces VSMC phenotypic transformation when IP receptors are impaired. This is attributed to the activation of TP receptor and its downstream signaling cascades, and to the increased membrane distribution of TP receptors. The VSMC detrimental effect of PGI2 medicated by IP dysfunction and TP activation might probably exacerbate vascular remodelling, accelerating cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Cardiac hypertrophy is a common pathological change found in various cardiovascular diseases. Although it has long been recognized as an important risk factor responsible for heart failure, there is still a lack of effective treatments in clinic. Chrysophanol is a natural compound with multiple biological activities and protective roles in the cardiovascular system. However, its potential effect on cardiac hypertrophy remains unclear. In the current study, we found that chrysophanol could protect against isoproterenol (ISO)‐induced cardiac hypertrophy both in vitro and in vivo. Increase of cell surface and hypertrophic marker expression induced by ISO in neonatal rat cardiomyocytes was downregulated by chrysophanol. Moreover, chrysophanol ameliorated the abnormal changes of cardiac structure and function in rats subjected to ISO injection, as shown by echocardiography and morphometry measurements. Further mechanistical investigation demonstrated that chrysophanol inhibited phosphorylation of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) induced by ISO. Nuclear translocation of STAT3 and transcription of downstream genes promoted by ISO treatment were also remarkably suppressed by chrysophanol. Taken together, our findings revealed that chrysophanol attenuated ISO‐induced cardiac hypertrophy by inhibiting JAK2/STAT3 signaling pathway. Chrysophanol may be a potential candidate compound for the prevention and treatment of hypertrophy‐related cardiomyopathy. [ABSTRACT FROM AUTHOR]

AMP-activated protein kinase (AMPK) is a central regulator of multiple metabolic pathways. It has been shown that activation of AMPK could inhibit fibroblast proliferation and extracellular matrix (ECM) accumulation, thereby suppressing cardiac fibrosis. Baicalin, the major component found in skullcap, possesses multiple protective effects on the cardiovascular system. However, little is known about the effect of baicalin on cardiac fibrosis and the molecular mechanism by which baicalin exerts its anti-fibrotic effects has not been investigated. In this study, we revealed that baicalin could inhibit cell proliferation, collagen synthesis, fibronectin (FN) and Connective tissue growth factor (CTGF) protein expression in cardiac fibroblasts induced by angiotensin Ⅱ (Ang Ⅱ). It also ameliorated cardiac fibrosis in rats submitted to abdominal aortic constriction (AAC). Moreover, baicalin inhibited transforming growth factor-β (TGF-β)/Smads signaling pathway stimulated with Ang Ⅱ through activating AMPK. Subsequently, we also demonstrated that baicalin attenuated Ang Ⅱ-induced Smad3 nuclear translocation, and interaction with transcriptional coactivator p300, but promoted the interaction of p300 and AMPK. Taken together, these results provide the first evidence that the effect of baicalin against cardiac fibrosis may be attributed to its regulation on AMPK/TGF-β/Smads signaling, suggesting the therapeutic potential of baicalin on the prevention of cardiac fibrosis and heart failure. [ABSTRACT FROM AUTHOR]

The creation of a high bond strength between machined computer-manufactured pure titanium and porcelain remains problematic, and the effects of a silica coating on the bond strength of milled pure titanium bonded to dental porcelain require further investigation. The objective of this study was to evaluate the bond strength of machined pure titanium, with an intermediate coating of silica, to dental porcelain. In this work, 24 specimens of milled pure titanium were prepared and randomly divided into test and control groups, in which the test group was coated with silica using the sol-gel dipping technique. The metal-ceramic bond strength was evaluated, according to ISO 9693 standards, using the three-point bending test, and scanning electron microscopy and energy-dispersive spectroscopy were used to study the microstructure and elemental composition of the specimens. The bonding strength of the silica-coated group was significantly higher than that of the control group, and more residual porcelain on the metal surface could be observed in the silica-coated group. Therefore, the application of a silica intermediate coating produced using the sol-gel method could significantly improve the bond strength between machined pure titanium and porcelain. [ABSTRACT FROM AUTHOR]

Background and Purpose: Cryptotanshinone (CTS) is a major bioactive diterpenoid isolated from Danshen, an eminent medicinal herb that is used to treat cardiovascular disorders in Asian medicine. However, it is not known whether CTS can prevent experimental atherosclerosis. The present study was designed to investigate the protective effects of CTS on atherosclerosis and its molecular mechanisms of action.Experimental Approach: Apolipoprotein E-deficient (ApoE(-/-)) mice, fed an atherogenic diet, were dosed daily with CTS (15, 45 mg kg(-1) day(-1)) by oral gavage. In vitro studies were carried out in oxidized LDL (oxLDL)-stimulated HUVECs treated with or without CTS.Key Results: CTS significantly attenuated atherosclerotic plaque formation and enhanced plaque stability in ApoE(-/-) mice by inhibiting the expression of lectin-like oxLDL receptor-1 (LOX-1) and MMP-9, as well as inhibiting reactive oxygen species (ROS) generation and NF-κB activation. CTS treatment significantly decreased the levels of serum pro-inflammatory mediators without altering the serum lipid profile. In vitro, CTS decreased oxLDL-induced LOX-1 mRNA and protein expression and, thereby, inhibited LOX-1-mediated adhesion of monocytes to HUVECs, by reducing the expression of adhesion molecules (intracellular adhesion molecule 1 and vascular cellular adhesion molecule 1). Furthermore, CTS inhibited NADPH oxidase subunit 4 (NOX4)-mediated ROS generation and consequent activation of NF-κB in HUVECs.Conclusions and Implications: CTS was shown to have anti-atherosclerotic activity, which was mediated through inhibition of the LOX-1-mediated signalling pathway. This suggests that CTS is a vasculoprotective drug that has potential therapeutic value for the clinical treatment of atherosclerotic cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Highlights: [•] Salvianolic acid B (SalB) protected cardiomyocytes from AngII-induced hypertrophy. [•] SalB’ anti-hypertrophy was partly attributed to its inhibition on PARP-1. [•] SalB prevented the depletion of cellular NAD+ induced by AngII. [•] SalB’s antioxidant effect might contribute to the inhibition of PARP-1. [ABSTRACT FROM AUTHOR]

Abstract: The pathogens of Alzheimer''s disease (AD) are still unclear, while accumulating evidences have indicated that both genetic and environmental factors are involved in the pathogenesis of AD. Recent studies suggest that AD is primarily a vascular disorder and copper (Cu) may play an important role in AD pathology. However, the consequences of chronic Cu exposure at the presence of other AD risk factors remain to be clarified. To investigate the effects of chronic Cu intake on cerebral hypoperfusion-induced AD pathology, Sprague-Dawley rats suffered bilateral common carotid artery occlusion (2VO) were administrated with 250ppm copper-containing water or not. Morris water maze test showed that Cu exposure for 3 months exacerbated cognitive impairment induced by 2VO. Elevated amyloid precursor protein (APP) and beta-site APP-cleaving enzyme 1 (BACE1) expression in mRNA and protein levels were also observed in brain of Cu-exposed rats suffered 2VO. In contrast, these Cu-exacerbated changes were ameliorated after Cu was withdrawn from drinking water. In summary, our findings demonstrate that chronic Cu exposure might exacerbate AD pathology in 2VO rats. [Copyright &y& Elsevier]

Highlights: [•] In cardiomyocytes, ET-1 treatment resulted in significant upregulation of COX-2 expression and activity. [•] Both COX-2 inhibitors and COX-2 RNA interference suppressed cardiomyocyte hypertrophy induced by ET-1. [•] Calcineurin/NFATc3 signaling pathway participated in the transcriptional regulation of COX-2 by ET-1. [ABSTRACT FROM AUTHOR]

Abstract Jumonji domain-containing protein D3 (JMJD3), a histone 3 lysine 27 (H3K27) demethylase, has been extensively studied for their participation in development, cellular physiology and a variety of diseases. However, its potential roles in cardiovascular system remain unknown. In this study, we found that JMJD3 played a pivotal role in the process of cardiac hypertrophy. JMJD3 expression was elevated by isoproterenol (ISO) stimuli both in vitro and in vivo. Overexpression of wild-type JMJD3, but not the demethylase-defective mutant, promoted cardiomyocyte hypertrophy, as implied by increased cardiomyocyte surface area and the expression of hypertrophy marker genes. In contrary, JMJD3 silencing or its inhibitor GSK-J4 suppressed ISO-induced cardiac hypertrophy. Mechanistically, JMJD3 was recruited to demethylate H3K27me3 at the promoter of β-MHC to promote its expression and cardiac hypertrophy. Thus, our results reveal that JMJD3 may be a key epigenetic regulator of β-MHC expression in cardiomyocytes and a potential therapeutic target for cardiac hypertrophy. Graphical abstract Image 1 Highlights • JMJD3 expression was significantly upregulated in ISO-induced cardiac hypertrophy in vitro and in vivo. • JMJD3 depletion or GSK-J4 treatment attenuated the hypertrophic responses stimulated by ISO. • JMJD3 overexpression led to cardiac hypertrophy. • JMJD3 was recruited to and demethylated H3K27me3 at the promoter of β-MHC to promote its expression and cardiac hypertrophy. [ABSTRACT FROM AUTHOR]

The Forkhead box-containing protein, O subfamily 3 (FoxO3) transcription factor negatively regulates myocardial hypertrophy, and its transcriptional activity is finely conditioned by diverse posttranslational modifications, such as phosphorylation, acetylation, ubiquitination, methylation and glycosylation. Here, we introduce a novel modification of the FoxO3 protein in cardiomyocytes: poly(ADP-ribosyl)ation (PARylation) mediated by poly(ADP-ribose) polymerase-1 (PARP1). This process catalyzes the NAD + -dependent synthesis of polymers of ADP-ribose (PAR) and their subsequent attachment to target proteins by PARPs. Primary-cultured neonatal rat cardiomyocytes were incubated with isoproterenol (ISO) to induce hypertrophy, or were infected with recombinant adenovirus vectors harboring PARP1 cDNA (Ad-PARP1). Sprague-Dawley (SD) rats were treated with ISO to induce cardiac hypertrophy, or were injected with Ad-PARP1 into the anterior and posterior left ventricular walls. Cardiomyocyte surface area, the mRNA expression of hypertrophic biomarkers, echocardiography, morphometry of the hearts were measured. The PARP1 activity was tested by cellular PAR levels. Interactions of PARP1 and FoxO3 were investigated by co-immunoprecipitation and immunofluorescence technique. PARylation of FoxO3 mediated by PARP1 facilitated its phosphorylation at the T32, S252 and S314 sites, triggered its nucleus export and suppressed its transcriptional activity and target genes expression, ultimately inducing cardiac hypertrophy. Additionally, PARP1 silencing or specific inhibition by 3-Aminobenzamide (3AB) and veliparib (ABT-888) alleviated the inhibition of FoxO3 activity by ISO, thus suppressing ISO-induced cardiac hypertrophy. Our data provide the first evidence that PARP1 exacerbates cardiac hypertrophy by PARylation of FoxO3. [ABSTRACT FROM AUTHOR]

Objective Tongue squamous cell carcinoma (TSCC) is the most common malignant cancer in the oral cavity, with a high rate of metastasis to the neck lymphoid node. Angiopoietin-like protein 4 (ANGPTL4) and microvessel density (MVD) may be novel indicators for tumor metastasis. The aim of the present study was to investigate the expression and function of ANGPTL4 in TSCC and the relationship between ANGPTL4 and MVD. Methods The expression levels of ANGPTL4 and MVD (CD34) were analyzed in 65 TSCC specimens and the adjacent non-cancerous tissues using immunohistochemistry (IHC). siRNA was delivered into TSCCA cells to downregulate ANGPTL4 expression. Subsequently, validation with real-time RT-PCR and western blot analyses was performed to analyze ANGPTL4 expression levels. In addition, a proliferation assay, migration and invasion assays were carried out. Results ANGPTL4 expression was associated with tumor stage, lymph node metastasis and MVD expression. Cox regression analysis showed that high levels of ANGPTL4 expression were closely associated with poor survival time. In vitro analyses using qRT-PCR and western blot confirmed that ANGPTL4 was successfully inhibited in TSCCA cells. Suppressing ANGPTL4 resulted in the inhibition of cell proliferation and migration, but neither invasion nor cisplatin resistance was significantly affected. Conclusion High expression levels of ANGPTL4 are associated with the T stage, lymphatic metastasis, angiogenesis and poor overall survival in TSCC patients. The downregulation of ANGPTL4 inhibits the migration and proliferation of cells in TSCC. Taken together, ANGPTL4 may serve as a novel biomarker and therapeutic target for TSCC. [ABSTRACT FROM AUTHOR]

Highlights: [•] C/EBPβ expression is upregulated in response to hypertrophic stimulation in vitro and in vivo. [•] C/EBPβ knockdown protects cardiomyocytes from hypertrophy. [•] C/EBPβ knockdown reduced the nuclear translocation of p65-NFκB, and diminished NFκB-DNA binding activity. [ABSTRACT FROM AUTHOR]

Highlights: [•] Fenofibrate ameliorates cardiac hypertrophy in vivo and in vitro. [•] The interaction between p65-NFκB and NFATc4 regulates cardiac hypertrophy. [•] Fenofibrate attenuates cardiac hypertrophy via activating PPAR-α and thereby preventing the association of p65-NFκB with NFATc4. [Copyright &y& Elsevier]

Abstract: Poly(ADP-ribosyl)ation catalyzed by the poly(ADP-ribose) polymerases (PARPs) is an immediate post-translational modification of proteins with a homopolymeric chain of repeating ADP-ribose units. It is involved in various cellular processes, such as cell survival and death, transcription, DNA repair and cell division. Inhibitors of PARPs have been documented to be useful in different pathological conditions. Recently, activation of PARP-1, the founding member of PARP family, has been revealed to participate in the development and progression of cardiac hypertrophy and heart failure. However, the roles of other PARPs in cardiovascular system remain to be clarified. PARP-2 shares 69% similarity with PARP-1 in catalytic domains, but their functions do not fully overlap. In this study, we show the first evidence that PARP-2 is involved in cardiac hypertrophy. The mRNA and protein levels of PARP-2 were significantly increased in AngII-stimulated rat cardiomyocytes as well as in hearts of rats submitted to pressure overload. PARP-2 knockdown protected cardiomyocytes from hypertrophy, which may be attributed to activation of SIRT1. These findings shed new light on the understanding of PARP-2-related cardiomyopathy, and suggest the potential application of PARP-2 inhibitors in cardiac hypertrophy. [Copyright &y& Elsevier]

Although histone lysine methylation has been extensively studied for their participation in pathological cardiac hypertrophy, the potential regulatory role of histone arginine methylation remains to be elucidated. The present study focused on H4R3 symmetric di-methylation (H4R3me2s) induced by protein arginine methyltransferase 5 (Prmt5), and explored its epigenetic regulation and underlying mechanisms in cardiomyocyte hypertrophy. 1. The expressions of Prmt5 and H4R3me2s were suppressed in cardiac hypertrophy models in vivo and in vitro ; 2. Prmt5 silencing or its inhibitor EPZ, or knockdown of cooperator of Prmt5 (Copr5) to disrupt H4R3me2s, facilitated cardiomyocyte hypertrophy, whereas overexpression of wild type Prmt5 rather than the inactive mutant protected cardiomyocytes against hypertrophy; 3. ChIP-sequence analysis identified Filip1L as a target gene of Prmt5-induced H4R3me2s; 4. Knockdown or inhibition of Prmt5 impaired Filip1L transcription and subsequently prevented β-catenin degradation, thus augmenting cardiomyocyte hypertrophy. The present study reveals that Prmt5-induced H4R3me2s ameliorates cardiomyocyte hypertrophy by transcriptional upregulation of Filip1L and subsequent enhancement of β-catenin degradation. Deficiency of Prmt5 and the resulting suppression of H4R3me2s might facilitate the development of pathological cardiac hypertrophy. Prmt5 might serve as a key epigenetic regulator in pathological cardiac hypertrophy. [ABSTRACT FROM AUTHOR]