Cardiac hypertrophy is an adaptive enlargement of myocardium in response to pressure overload caused various pathological insults, which is accompanied by alteration of a complex cascade of signaling ...pathways. During the hypertrophy process, many changes occur at cellular level including gene reprogramming by turning off chromatin regulators. Studies from the past decade have demonstrated that the abnormal epigenetic modifications, such as DNA methylation, histone modification, and oxidative modification of nucleic acid, could lead to changes in chromosome structure and cardiac dysfunction. Increasing evidence indicates that non-coding RNAs (ncRNAs) have functional significance in modulating the gene expression during those pathological events in the heart. Emerging evidences have highlighted that ncRNAs might serve as a signal for changing the state of chromatin, however, the knowledge about the ncRNA-linked epigenetic regulatory mechanisms in cardiac pathologies is still largely unexplored. In this review, we summarize the current information on association between ncRNAs and epigenetic modifications in cardiac hypertrophy, and we have discussed their crosstalk. In addition, this review provides insights into their therapeutic and diagnostic potential for treating hypertrophic heart disease.
The role of Abraxas 2 (ABRO1 or KIAA0157), a component of the lysine63-linked deubiquitinating system, in the cardiomyocyte proliferation and myocardial regeneration is unknown. Here, we found that ...ABRO1 regulates cardiomyocyte proliferation and cardiac regeneration in the postnatal heart by targeting METTL3-mediated m6A methylation of Psph mRNA. The deletion of ABRO1 increased cardiomyocyte proliferation in hearts and restored the heart function after myocardial injury. On the contrary, ABRO1 overexpression significantly inhibited the neonatal cardiomyocyte proliferation and cardiac regeneration in mouse hearts. The mechanism by which ABRO1 regulates cardiomyocyte proliferation mainly involved METTL3-mediated Psph mRNA methylation and CDK2 phosphorylation. In the early postnatal period, METTL3-dependent m6A methylation promotes cardiomyocyte proliferation by hypermethylation of Psph mRNA and upregulating PSPH expression. PSPH dephosphorylates cyclin-dependent kinase 2 (CDK2), a positive regulator of cell cycle, at Thr14/Tyr15 and increases its activity. Upregulation of ABRO1 restricts METTL3 activity and halts the cardiomyocyte proliferation in the postnatal hearts. Thus, our study reveals that ABRO1 is an essential contributor in the cell cycle withdrawal and attenuation of proliferative response in the postnatal cardiomyocytes and could act as a potential target to accelerate cardiomyocyte proliferation and cardiac repair in the adult heart.
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Downregulation of ABRO1 promotes METTL3 activity and cardiomyocyte proliferation in the postnatal heart. METTL3 promotes m6A methylation of Psph mRNA and increases PSPH expression. PSPH dephosphorylates cyclin-dependent kinase 2 (CDK2), a positive regulator of cell cycle, at Thr14/Tyr15, increases its activity, and induces cardiomyocyte proliferation.
Our recent studies showed that contents of necrotic renal proximal tubular cells (RPTC) from 2 × 10(6) cells/ml directly induced death of cultured renal interstitial fibroblasts. However, it remains ...unknown whether nonlethal number of necrotic RPTC would also alter the fate of renal interstitial fibroblasts. To address this issue, renal interstitial fibroblasts (NRK-49F) were exposed to necrotic RPTC supernatant (RPTC-Sup) obtained from 2 × 10(4) to 5 × 10(5) cells/ml. These concentrations of RPTC did not induce cell death, but led to inactivation of renal fibroblasts as indicated by reduced expression of α-smooth muscle actin and fibronectin, two hallmarks of activated fibroblasts. Concurrently, the same doses of necrotic RPTC-Sup suppressed phosphorylation of epidermal growth factor receptor (EGFR) and signal transducers and activators of transcription-3 (STAT3) in a time- and dose-dependent manner, but did not affect phosphorylation of platelet-derived growth factor receptor-β, AKT, and extracellular signal-regulated kinase 1/2. The presence of sodium orthovanadate, a general protein tyrosine phosphatase (PTP) inhibitor or TCS-401 (a selective PTP1B inhibitor), abrogated those effects of RPTC-Sup, whereas coincubation with the EGFR inhibitor (Gefitinib) or silencing of EGFR with siRNA preserved the ability of RPTC-Sup in suppressing renal fibroblast activation and STAT3 phosphorylation. Moreover, RPTC-Sup treatment induced PTP1B phosphorylation and its interaction with EGFR. Collectively, these results indicate that nonlethal necrotic RPTC-Sup can induce inactivation of renal interstitial fibroblasts, which occurs through a mechanism involved in PTP1B-mediated inhibition of EGFR signaling.
This study examines the antioxidant and teratogenic effects of two different type’s methods of formulating agar from Turbinaria conoides (T. conoides) using a zebrafish model. The agar was extracted ...using the aqueous extraction method and developed in two different formulations using separate procedures. Formulated agar1 (FA1) used a higher concentration of the ingredients while formulated agar 2 (FA2) had a lesser concentration. The two unique formulated agars (FAs) were studied using biochemical composition, Fourier infrared (FT-IR) spectroscopy, gas chromatography-mass spectroscopy (GC-MS), and scanning electron microscopy (SEM). The antioxidant activities of both FAs in vitro were shown to be significantly different (P<0.05) at various concentrations (60–180 μl/ml) in the study. The toxicity of the FAs was dose-dependent, with FA1 having the least teratogenic activity when compared to FA2. In comparison to FA2, FA1 was found to have higher antioxidant activity. At various concentrations (0.5, 0.25, and 0.125 μg/ml), the teratogenic activity of two FAs was examined in zebrafish embryos (ZFE) at 24, 48, 72, and 96 hours post fertilization (hpf). Both FAs exhibit dose-dependent toxicity and increased antioxidant activity, and this can be utilized as an alternative for standard antioxidants, according to this study.
Although activation of sirtuin-1 (SIRT1) has been shown to protect the kidney from acute injury, its role in renal fibrosis remains controversial since both inhibition and activation of SIRT1 have ...been reported to attenuate renal fibrosis. To resolve this conflict, we further examined the effect of SIRT1 activators on the activation of renal interstitial fibroblasts and development of renal fibrosis in vivo and in vitro. In a murine model of renal fibrosis induced by unilateral ureteral obstruction, administration of SRT1720 (N-2-3-(piperazin-1-ylmethyl)imidazo2,1-b1,3thiazol-6-ylphenylquinoxaline-2-carboxamide), a potent activator of SIRT1, accelerated deposition of collagen fibrils and increased expression of fibroblast activation markers (α-smooth muscle actin α-SMA, collagen I, and fibronectin) in the obstructive kidney of mice. In cultured rat renal interstitial fibroblasts (NRK-49F), exposure of cells to SRT1720 or YK-3-237 (B-2-methoxy-5-(1E)-3-oxo-3-(3,4,5-trimethoxyphenyl)-1-propen-1-ylphenyl-boronic acid), another SIRT1 activator, also resulted in enhanced expression of α-SMA and fibronectin. Mechanistic studies showed that augmentation of renal fibrogenesis by SRT1720 is associated with elevated phosphorylation of epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor β (PDGFRβ). SRT1720 treatment also increased the phosphorylation of signal transducer and activator of transcription 3 and protein kinase B in the fibrotic kidney and NRK-49F cells. However, SRT1720 treatment did not affect expression of proliferating cell nuclear protein, a proliferation marker and activation of extracellular signal regulated kinase 1/2 in vitro and in vivo. These results indicate that SIRT1-activating compounds can provoke renal fibrogenesis through a mechanism involved in the activation of EGFR and PDGFR signaling pathways and suggest that long-term use of SIRT1 activators risks the development and progression of chronic kidney disease.
The activation of cytokine and growth factor receptors associates with the development and progression of renal fibrosis. Suramin is a compound that inhibits the interaction of several cytokines and ...growth factors with their receptors, but whether suramin inhibits the progression of renal fibrosis is unknown. Here, treatment of cultured renal interstitial fibroblasts with suramin inhibited their activation induced by TGF-β1 and serum. In a mouse model of obstructive nephropathy, administration of a single dose of suramin immediately after ureteral obstruction abolished the expression of fibronectin, largely suppressed expression of α-SMA and type I collagen, and reduced the deposition of extracellular matrix proteins. Suramin also decreased the expression of multiple cytokines including TGF-β1 and reduced the interstitial infiltration of leukocytes. Moreover, suramin decreased expression of the type II TGF-β receptor, blocked phosphorylation of the EGF and PDGF receptors, and inactivated several signaling pathways associated with the progression of renal fibrosis. In a rat model of CKD, suramin abrogated proteinuria, limited the decline of renal function, and prevented glomerular and tubulointerstitial damage. Collectively, these findings indicate that suramin is a potent antifibrotic agent that may have therapeutic potential for patients with fibrotic kidney diseases.
A number of miRNAs have been reported to be critically involved in the regulation of cardiovascular disease (CVDs). Therefore, the development of potent analogues/inhibitors for miRNAs have thus ...become a key focus in the present drug discovery. In this review, we discuss the basic research and clinical use of miRNAs as the early diagnosis and therapeutic targets for CVD. We have also focused on the efficiency of therapeutically targeting miR-499, which is considered as one of the most promising molecules for treating CVDs. Areas covered: In this review, we have discussed the patents and patent applications related to miRNAs detected in CVD patients published in recent years. This review also covers the expression pattern of miR-499, as well as it highlights functions of its inhibitors in CVD. We used Google and Pubmed search engines to find relevant patents. Expert opinion: Although a massive number of miRNAs are patented as CVD biomarkers, further work is absolutely required to evaluate the reliable diagnostic values and therapeutic potential of these candidates. Overall, targeting miRNAs is definitely a promising strategy to be investigated for diagnosis and treatment of CVDs in future, however, the delivery system and off-targets effects are still a difficult challenge need to be elucidated.
Approximately 2% of the human genome consists of protein-coding regions. Therefore, the majority of transcripts are noncoding RNAs, such as microRNA (miRNA) and long noncoding RNAs (lncRNAs). In ...ischemic heart disease, the majority of miRNAs are repressors or destabilizers of target messenger RNAs. The lncRNAs are a second class of noncoding RNAs that have recently gained attention for their roles in heart disease and in regulating the functions of miRNA. In this review, we summarize the role of miRNA in pathological cardiac hypertrophy and myocardial infarction. In addition, we discuss the functional interactions of miRNA and lncRNA and its impact on these ischemic heart diseases.
We recently reported that necrotic renal proximal epithelial cells (RPTC) stimulate the expression of P2X7 receptor in renal fibroblasts and that P2X7 receptor mediates deleterious ...epithelial-fibroblast cross talk. The present study was carried out to investigate the signaling mechanism of necrotic RPTC-induced P2X7 expression in cultured renal interstitial fibroblasts (NRK-49F). Exposure of NRK-49F to necrotic RPTC supernatant (RPTC-Sup) induced a time- and dose-dependent phosphorylation of several signaling pathways including extracellular signal-regulated kinases (ERK1/2), p38, c-Jun N-terminal kinases (JNKs), and AKT in NRK-49F. Pharmacological inhibition of ERK1/2, but not p38, JNK, and AKT pathways, blocked RPTC-Sup-induced P2X7 expression and renal interstitial fibroblast death. Knockdown of ERK1/2 or MEK1, a direct upstream activator of ERK1/2, also reduced RPTC-Sup-induced P2X7 expression and cell death of renal fibroblasts. Conversely, overexpression of MEK1 enhanced these responses. Upon necrotic RPTC exposure, phosphorylation of Elk1, a transcriptional factor targeted by ERK1/2, was increased in NRK-49F, and knockdown of Elk1 by siRNA remarkably reduced RPTC-Sup-induced P2X7 expression as well as renal fibroblast death. Furthermore, silencing of MEK1 inhibited Elk1 phosphorylation in response to necrotic RPTC, whereas overexpression of MEK1 increased Elk1 phosphorylation. Taken together, these data reveal that necrotic RPTC induces P2X7 expression in renal fibroblasts through activation of the MEK1-ERK1/2-Elk1 signaling pathway.
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