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Pubblicazioni recenti - cardiac hypertrophy
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The Interstitium in the Hypertrophied Heart.
JACC Cardiovasc Imaging2019 Sep;():. doi: S1936-878X(19)30714-4.
Halliday Brian P, Prasad Sanjay K,
Abstract
Pathological left ventricular hypertrophy is a common feature of many cardiac diseases. It results from both myocyte hypertrophy and interstitial expansion. Interstitial expansion is most commonly secondary to the accumulation of mature cross-linked collagen fibers due to dysregulated metabolism, known as interstitial fibrosis. This occurs secondary to a variety of stimuli including ischemic, toxic, metabolic, infective, genetic, and hemodynamic factors. Less commonly, interstitial expansion may occur because of the accumulation of misfolded amyloid protein or interstitial edema. It is now well recognized that the presence and extent of interstitial disease are associated with adverse outcomes. There is therefore interest in the development of novel therapies that target the pathways that drive these disease processes. With the emergence of such therapies, it is becoming increasingly important to be able to characterize the type and extent of interstitial disease to enable the use of such targeted therapies in a personalized manner.
Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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Detection of de novo del(18)(q22.2) and a familial of 15q13.2-q13.3 microduplication in a fetus with congenital heart defects.
Taiwan J Obstet Gynecol2019 Sep;58(5):704-708. doi: S1028-4559(19)30177-9.
Chen Chih-Ping, Chen Chen-Yu, Chern Schu-Rern, Wu Peih-Shan, Chen Shin-Wen, Wu Fang-Tzu, Chen Li-Feng, Wang Wayseen,
Abstract
OBJECTIVE:
We present detection of de novo del(18)(q22.2) and a familial 15q13.2-q13.3 microduplication in a fetus with congenital heart defects (CHD).
CASE REPORT:
A 27-year-old, primigravid woman was referred for genetic counseling because of fetal CHD. Prenatal ultrasound at 17 weeks of gestation revealed pericardial effusion, cardiomegaly and a large ventricular septal defect. The pregnancy was subsequently terminated at 18 weeks of gestation, and a 192-g female fetus was delivered with facial dysmorphism. Cytogenetic analysis of the umbilical cord revealed a karyotype of 46,XX,del(18)(q22.2). The parental karyotypes were normal. Array comparative genomic hybridization (aCGH) of the placental tissue revealed a 2.08-Mb 15q13.2-q13.3 microduplication encompassing KLF13 and CHRNA7, and a 10.74-Mb 18q22.2-q23 deletion encompassing NFATC1. The phenotypically normal father carried the same 2.08-Mb 15q13.2-q13.3 microduplication. Polymorphic DNA marker analysis confirmed a paternal origin of the distal 18q deletion.
CONCLUSION:
Prenatal diagnosis of CHD should include a complete genetic study of the embryonic tissues, and the acquired information is useful for genetic counseling.
Copyright © 2019. Published by Elsevier B.V.
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FKBP52 regulates TRPC3-dependent Ca signals and the hypertrophic growth of cardiomyocyte cultures.
J Cell Sci2019 Sep;():. doi: jcs.231506.
Bandleon Sandra, Strunz Patrick P, Pickel Simone, Tiapko Oleksandra, Cellini Antonella, Miranda-Laferte Erick, Eder-Negrin Petra,
Abstract
The Transient receptor potential (TRP; C-classical; TRPC) channel TRPC3 permeates a cation (Na/Ca) influx that is favoured by the stimulation of G protein-coupled receptors (GPCRs). An enhanced TRPC3 activity is related to adverse effects including pathological hypertrophy in chronic cardiac disease states. In the present study we identified FK506 binding protein 52 (FKBP52) as a novel interaction partner of TRPC3 in the heart. FKBP52 was recovered from a cardiac cDNA library by a C-terminal TRPC3 fragment (amino acids 742-848) in a yeast two-hybrid screen. Downregulation of FKBP52 promoted a TRPC3-dependent hypertrophic response in neonatal rat cardiomyocytes (NRC). A similar effect was achieved by overexpressing PPIase-deficient FKBP52 mutants. Mechanistically, FKBP52 truncated mutants elevated TRPC3-mediated currents and Ca fluxes, the activation of calcineurin and the nuclear factor of activated T-cells in NRCs. Our data demonstrate that FKBP52 associates with TRPC3 an as yet undescribed binding site in the C-terminus of TRPC3 and modulates TRPC3-dependent Ca signals in a PPIase-dependent manner. This functional interaction might be crucial for limiting TRPC3-dependent signaling during chronic hypertrophic stimulation.
© 2019. Published by The Company of Biologists Ltd.
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FGF23-Mediated Activation of Local RAAS Promotes Cardiac Hypertrophy and Fibrosis.
Int J Mol Sci2019 Sep;20(18):. doi: E4634.
Böckmann Ineke, Lischka Jonas, Richter Beatrice, Deppe Jennifer, Rahn Anja, Fischer Dagmar-Christiane, Heineke Jörg, Haffner Dieter, Leifheit-Nestler Maren,
Abstract
Patients with chronic kidney disease (CKD) are prone to developing cardiac hypertrophy and fibrosis, which is associated with increased fibroblast growth factor 23 (FGF23) serum levels. Elevated circulating FGF23 was shown to induce left ventricular hypertrophy (LVH) via the calcineurin/NFAT pathway and contributed to cardiac fibrosis by stimulation of profibrotic factors. We hypothesized that FGF23 may also stimulate the local renin-angiotensin-aldosterone system (RAAS) in the heart, thereby further promoting the progression of FGF23-mediated cardiac pathologies. We evaluated LVH and fibrosis in association with cardiac FGF23 and activation of RAAS in heart tissue of 5/6 nephrectomized (5/6Nx) rats compared to sham-operated animals followed by in vitro studies with isolated neonatal rat ventricular myocytes and fibroblast (NRVM, NRCF), respectively. Uremic rats showed enhanced cardiomyocyte size and cardiac fibrosis compared with sham. The cardiac expression of and RAAS genes were increased in 5/6Nx rats and correlated with the degree of cardiac fibrosis. In NRVM and NRCF, FGF23 stimulated the expression of RAAS genes and induced indicating mineralocorticoid receptor activation. The FGF23-mediated hypertrophic growth of NRVM and induction of NFAT target genes were attenuated by cyclosporine A, losartan and spironolactone. In NRCF, FGF23 induced and , which were suppressed by losartan and spironolactone, only. Our data suggest that FGF23-mediated activation of local RAAS in the heart promotes cardiac hypertrophy and fibrosis.
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Taxifolin ameliorates DEHP-induced cardiomyocyte hypertrophy via attenuating mitochondrial dysfunction and glycometabolism disorder in chicken.
Environ Pollut2019 Sep;255(Pt 1):113155. doi: S0269-7491(19)34362-3.
Cai Jingzeng, Shi Guangliang, Zhang Yuan, Zheng Yingying, Yang Jie, Liu Qi, Gong Yafan, Yu Dahai, Zhang Ziwei,
Abstract
Di-(2-ethylhexyl) phthalate (DEHP) is a prevalent environmental contaminant that severely impacts the health of human and animals. Taxifolin (TAX), a plant flavonoid isolated from yew, exerts protective effects on cardiac diseases. Nevertheless, whether DEHP could induce cardiomyocyte hypertrophy and its mechanism remains unclear. This study aimed to highlight the specific molecular mechanisms of DEHP-induced cardiomyocyte hypertrophy and the protective potential of TAX against it. Chicken primary cardiomyocytes were treated with DEHP (500??M) and/or TAX (0.5??M) for 24?h. The levels of glucose and adenosine triphosphate (ATP) were detected, and cardiac hypertrophy-related genes were validated by real-time quantitative PCR (qRT-PCR) and Western blot (WB) in vitro. The results showed that DEHP-induced cardiac hypertrophy was ameliorated by TAX, as indicated by the increased cardiomyocyte area and expression of atrial natriuretic peptide (ANP), natriuretic peptides A-like (BNP) and ?-myosin heavy cardiac muscle (?-MHC). Furthermore, DEHP induced cardiac hypertrophy via the interleukin 6 (IL-6)/Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathway in vitro. In addition, DEHP disrupted mitochondrial function and glycometabolism by activating the insulin-like growth factor 1 (IGF1)/phosphatidylinositol 3-kinase (PI3K) pathway and the peroxisome proliferator activated receptors (PPARs)/PPARG coactivator 1 alpha (PGC-1?) pathway to induce cardiac hypertrophy in vitro. Intriguingly, those DEHP-induced changes were obviously alleviated by TAX treatment. Taken together, cardiac hypertrophy was induced by DEHP via activating the IL-6/JAK/STAT3 signaling pathway, triggering glycometabolism disorder and mitochondrial dysfunction in vitro, can be ameliorated by TAX. Our findings may provide a feasible molecular mechanism for the treatment of cardiomyocyte hypertrophy induced by DEHP.
Copyright © 2019 Elsevier Ltd. All rights reserved.
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Long noncoding RNA Chaer mediated Polycomb Repressor Complex 2 (PRC2) activity to promote atherosclerosis through mTOR signaling.
Eur Rev Med Pharmacol Sci2019 Sep;23(17):7639-7648. doi: 18887.
Li F-P, Ling D-Q, Gao L-Y,
Abstract
OBJECTIVE:
Recent studies highlighted long noncoding RNAs (lncRNAs) have been implicated in many biological processes and diseases. However, atherosclerosis is a major risk factor for cardiovascular disease, but the detailed mechanism of atherosclerosis progression remained unclear. In this study, we mainly focused on the role of lncRNA Chaer in atherosclerosis.
PATIENTS AND METHODS:
RT-PCR was used to detect the expression of lncRNA Chaer in atherosclerosis patients and animal model. Moreover, the expression of Chaer in vascular smooth muscle cell dysfunction model was also measured. Proliferation ability was tested by CCK-8 and cyclin D1 assay, through loss- and gain-of-function approaches. Western-blot was used to measure the expression of H3 lysine 27 methylation, when Chaer was in different levels. RIP and ChIP assay discovered an interaction between Chaer and PRC2 through mTOR signaling.
RESULTS:
Here we identified a heart-enriched long non-coding RNA, named Cardiac Hypertrophy Associated Epigenetic Regulator (Chaer). We found that the Chaer was highly expressed in serum samples from 28 patients with atherosclerosis, compared with 28 healthy volunteers. Chaer was dramatically upregulated in atherosclerotic plaques of ApoE-/- mice. We also found that the expression of Chaer was upregulated in vascular smooth muscle cell injury model. Through loss- and gain-of-function approaches, we showed that Chaer promotes cell proliferation and induces apoptosis in vitro. Mechanistically, Chaer interacts with Polycomb Repressor Complex 2 (PRC2) through inhibiting histone H3 lysine 27 methylation. Further, this interaction is induced upon mTOR signaling pathway.
CONCLUSIONS:
According to the results, we found that lncRNA Chaer was closely related to the progression of atherosclerosis, which could be a previously uncharacterized lncRNA-dependent epigenetic checkpoint.
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Interleukin enhancement binding factor 3 inhibits cardiac hypertrophy by targeting asymmetric dimethylarginine-nitric oxide.
Nitric Oxide2019 Sep;():. doi: S1089-8603(19)30039-4.
Yang Ruo-Han, Tan Xing, Ge Lian-Jie, Sun Jia-Cen, Peng Xiao-Dong, Wang Wei-Zhong,
Abstract
Persistent cardiac hypertrophy eventually leads to deterioration of heart function and changes to normal morphology. Decreased nitric oxide (NO) production plays a critical role in modulating cardiac hypertrophy. Interleukin enhancement binding factor 3 (ILF3), a member of the double-stranded RNA-binding protein family, is known to regulate the transcription and stability of mRNA. Therefore, the major aim of the present study was to determine the role of ILF3 in reduction of NO production in cardiac hypertrophy. Cardiac hypertrophy models of neonatal rat cardiomyocytes (NRCMs) and adult rats were induced by angiotensin II (Ang II) in this study. First, it was found that ILF3 expression, NO production, and nitric oxide synthase (NOS) activity was decreased in cultured cardiomyocytes and adult rats treated with Ang II, compared with NRCMs treated with vehicle and rats treated with saline infusion, respectively. These effects induced by Ang II were significantly exacerbated by specific ILF3 knockdown. Moreover, the level of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NOS, was increased significantly in the Ang II-induced hypertrophic NRCMs and adult rats. Additionally, decreased protein expression and mRNA level of dimethylarginine dimethylaminohydrolases 1 (DDAH1, which degrades ADMA) were observed. Furthermore, specific ILF3 knockdown further aggravated these effects, but didn't reduce the expression level of NOS isoforms. In conclusion, our data show that ADMA accumulation-mediated decrease in NO production plays an important role in cardiomyocyte remodeling, which may be associated with ILF3-mediated DDAH1 reduction.
Copyright © 2019. Published by Elsevier Inc.
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A knock-in mutation at cysteine 144 of TRIM72 is cardioprotective and reduces myocardial TRIM72 release.
J Mol Cell Cardiol2019 Sep;():. doi: S0022-2828(19)30190-7.
Fillmore Natasha, Casin Kevin M, Sinha Prithvi, Sun Junhui, Ma Hanley, Boylston Jennifer, Noguchi Audrey, Liu Chengyu, Wang Nadan, Zhou Guangshuo, Kohr Mark J, Murphy Elizabeth,
Abstract
TRIM72 is a membrane repair protein that protects against ischemia reperfusion (I/R) injury. We previously identified Cys (C144) on TRIM72 as a site of S-nitrosylation. To study the importance of C144, we generated a knock-in mouse with C144 mutated to a serine (TRIM72 C144S). We subjected ex vivo perfused mouse hearts to 20?min of ischemia followed by 90?min of reperfusion and observed less injury in TRIM72 C144S compared to WT hearts. Infarct size was smaller (54 vs 27% infarct size) and cardiac functional recovery (37 vs 62% RPP) was higher for the TRIM72 C144S mouse hearts. We also demonstrated that TRIM72 C144S hearts were protected against I/R injury using an in vivo LAD occlusion model. As TRIM72 has been reported to be released from muscle we tested whether C144 is involved in TRIM72 release. After I/R there was significantly less TRIM72 in the perfusate normalized to total released protein from the TRIM72 C144S compared to WT hearts, suggesting that C144 of TRIM72 regulates myocardial TRIM72 release during I/R injury. In addition to TRIM72's protective role in I/R injury, TRIM72 has also been implicated in cardiac hypertrophy and insulin resistance, and secreted TRIM72 has recently been shown to impair insulin sensitivity. However, insulin sensitivity (measured by glucose and insulin tolerance) of TRIM72 C144S mice was not impaired. Further, whole body metabolism, as measured using metabolic cages, was not different in WT vs TRIM72 C144S mice and we did not observe enhanced cardiac hypertrophy in the TRIM72 C144S mice. In agreement, protein levels of the TRIM72 ubiquitination targets insulin receptor ?, IRS1, and focal adhesion kinase were similar between WT and TRIM72 C144S hearts. Overall, these data indicate that mutation of TRIM72 C144 is protective during I/R and reduces myocardial TRIM72 release without impairing insulin sensitivity or enhancing the development of hypertrophy.
Copyright © 2018. Published by Elsevier Ltd.
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Cardiac Inflammation after Ischemia-Reperfusion of the Kidney: Role of the Sympathetic Nervous System and the Renin-Angiotensin System.
Cell Physiol Biochem2019 ;53(4):587-605. doi: 10.33594/000000159.
Panico Karine, Abrahão Mariana V, Trentin-Sonoda Mayra, Muzi-Filho Humberto, Vieyra Adalberto, Carneiro-Ramos Marcela S,
Abstract
BACKGROUND/AIMS:
To investigate the role of the sympathetic nervous system (SNS) and renin-angiotensin system (RAS) in renal ischemia/reperfusion-induced (I/R) cardiac inflammatoryprofile.
METHODS:
Left kidney ischemia was induced in male C57BL/6 mice for 60 min, followed by reperfusion for 12 days, and treatment with or without atenolol, losartan, or enalapril. The expression of vimentin in kidney and atrial natriuretic factor (ANF) in the heart has been investigated by RT-PCR. In cardiac tissue, levels of ?-adrenoreceptors, adenylyl cyclase, cyclic AMP-dependent protein kinase (PKA), noradrenaline, adrenaline (components of SNS), type 1 angiotensin II receptors (ATR), angiotensinogen/Ang II and renin (components of RAS) have been measured by Western blotting and HPLC analysis. A panel of cytokines - tumour necrosis factor (TNF-?), interleukin IL-6, and interferon gamma (IFN-?) - was selected as cardiac inflammatory markers.
RESULTS:
Renal vimentin mRNA levels increased by >10 times in I/R mice, indicative of kidney injury. ANF, a marker of cardiac lesion, increased after renal I/R, the values being restored to the level of Sham group after atenolol or enalapril treatment. The cardiac inflammatory profile was confirmed by the marked increase in the levels of mRNAs of TNF-?, IL-6, and IFN-?. Atenolol and losartan reversed the upregulation of TNF-? expression, whereas enalapril restored IL-6 levels to Sham levels; both atenolol and enalapril normalized IFN-? levels. I/R mice showed upregulation of ?-adrenoreceptors, adenylyl cyclase, PKA and noradrenaline. Renal I/R increased cardiac levels of ATR, which decreased after losartan or enalapril treatment. Renin expression also increased, with the upregulation returning to Sham levels after treatment with SNS and RAS blockers. Angiotensinogen/Ang II levels in heart were unaffected by renal I/R, but they were significantly decreased after treatment with losartan and enalapril, whereas increase in renin levels decreased.
CONCLUSION:
Renal I/R-induced cardiac inflammatory events provoked by the simultaneous upregulation of SNS and RAS in the heart, possibly underpin the mechanism involved in the development of cardiorenal syndrome.
© Copyright by the Author(s). Published by Cell Physiol Biochem Press.
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Adenine decreases hypertrophic effects through interleukin-18 receptor.
Chin J Physiol;62(4):139-147. doi: 10.4103/CJP.CJP_18_19.
Yang Yi-Feng, Liang Yao-Jen,
Abstract
Cardiac hypertrophy is the main cause of heart failure. Levels of circulating interleukin-18 (IL-18) have been reported to increase in congestive heart disease and cardiac hypertrophy. Relationships among IL-18 levels, IL-18 receptor (IL-18R) expression, and cardiac hypertrophy remain unclear. IL-18 can induce cardiac hypertrophy in cardiomyoblasts. We also studied IL-18R messenger RNA (mRNA) and protein expression through quantitative-polymerase chain reaction and Western blotting. Furthermore, we treated cardiomyoblasts with adenine, gold nanoparticles (AuNPs), and inhibitors to analyze the morphology and identify signaling pathways involved in cardiac hypertrophy. Moreover, we studied the effects of IL-18R small interfering RNA (siRNA) on signaling pathways through Western blotting. The mRNA expression of IL-18R in H9c2 cardiomyoblasts, which was induced by IL-18, increased significantly after 8 h, and the protein level increased significantly after 15 h. Morphological examination of H9c2 cardiomyoblasts showed that cell volume and cell diameter decreased after adenine pretreatment. Both p38 MAPK and PI3 kinase are biomarkers in the pathway correlated with cardiac hypertrophy. After treatment with inhibitors SB203580 and LY294002, the levels of p38 MAPK and PI3 kinase, respectively, decreased along with cell size and IL-18R expression. Treatment with adenine, but not AuNPs, reduced the levels of phosphorylated p38 and PI3 kinase expression more effectively than did treatment with the respective inhibitors alone. IL-18R siRNA significantly reduced cell size but not PI3 kinase expression and phosphorylation of p38 MAPK. However, adenine treatment reduced PI3 kinase expression after treatment with IL-18R siRNA. In this study, IL-18 induced cardiomyoblast hypertrophy through IL-18R upregulation, which was found to be related to p38 MAPK and PI3 kinase signaling. Adenine, but not AuNPs, showed antihypertrophic effects possibly because of decreased levels of signaling.
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The heart of a hibernator: EGFR and MAPK signaling in cardiac muscle during the hibernation of thirteen-lined ground squirrels, .
PeerJ2019 ;7():e7587. doi: 10.7717/peerj.7587.
Childers Christine L, Tessier Shannon N, Storey Kenneth B,
Abstract
Background:
Thirteen-lined ground squirrels ( experience dramatic changes in physiological and molecular parameters during winter hibernation. Notably, these animals experience reduced blood circulation during torpor, which can put numerous stresses on their hearts. The present study evaluates the role played by the epidermal growth factor receptor (EGFR) in signal transduction during hibernation at low body temperature to evaluate signaling mechanisms. By investigating the regulation of intracellular mitogen activated protein kinase (MAPK) pathway responses, anti-apoptosis signals, downstream transcription factors, and heat shock proteins in cardiac muscle we aim to determine the correlation between upstream tyrosine phosphorylation events and downstream outcomes.
Methods:
Protein abundance of phosphorylated EGFR, MAPKs and downstream effector proteins were quantified using immunoblotting and Luminex multiplex assays.
Results:
Monitoring five time points over the torpor/arousal cycle, EGFR phosphorylation on T654, Y1068, Y1086 was found to increase significantly compared with euthermic control values particularly during the arousal process from torpor, whereas phosphorylation at Y1045 was reduced during torpor. Phosphorylation of intracellular MAPK targets (p-ERK 1/2, p-JNK, p-p38) also increased strongly during the early arousal stage with p-p38 levels also rising during prolonged torpor. However, of downstream MAPK effector kinases that were measured, only p-Elk-1 levels changed showing a decrease during interbout arousal (IA). Apoptosis markers revealed a strong reduction of the pro-apoptotic p-BAD protein during entrance into torpor that remained suppressed through torpor and IA. However, active caspase-9 protein rose strongly during IA. Levels of p-AKT were suppressed during the transition phases into and out of torpor. Of four heat shock proteins assessed, only HSP27 protein levels changed significantly (a 40% decrease) during torpor.
Conclusion:
We show evidence of EGFR phosphorylation correlating to activation of MAPK signaling and downstream p-ELK1 suppression during hibernation. We also demonstrate a reduction in p-BAD mediated pro-apoptotic signaling during hibernation with active caspase-9 protein levels increasing only during IA. has natural mechanisms of tissue protection during hibernation that is largely due to cellular regulation through phosphorylation-mediated signaling cascade. We identify a possible link between EGFR and MAPK signaling via p-ERK, p-p38, and p-JNK in the cardiac muscle of these hibernating mammals that correlates with an apparent reduction in caspase-9 apoptotic signaling. This reveals a piece of the mechanism behind how these mammals are resilient to cardiac stresses during hibernation that would otherwise be damaging.
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Nuclear receptor corepressor 1 represses cardiac hypertrophy.
EMBO Mol Med2019 Sep;():e9127. doi: 10.15252/emmm.201809127.
Li Chao, Sun Xue-Nan, Chen Bo-Yan, Zeng Meng-Ru, Du Lin-Juan, Liu Ting, Gu Hui-Hui, Liu Yuan, Li Yu-Lin, Zhou Lu-Jun, Zheng Xiao-Jun, Zhang Yu-Yao, Zhang Wu-Chang, Liu Yan, Shi Chaoji, Shao Shuai, Shi Xue-Rui, Yi Yi, Liu Xu, Wang Jun, Auwerx Johan, Wang Zhao V, Jia Feng, Li Ruo-Gu, Duan Sheng-Zhong,
Abstract
The function of nuclear receptor corepressor 1 (NCoR1) in cardiomyocytes is unclear, and its physiological and pathological implications are unknown. Here, we found that cardiomyocyte-specific NCoR1 knockout (CMNKO) mice manifested cardiac hypertrophy at baseline and had more severe cardiac hypertrophy and dysfunction after pressure overload. Knockdown of NCoR1 exacerbated whereas overexpression mitigated phenylephrine-induced cardiomyocyte hypertrophy. Mechanistic studies revealed that myocyte enhancer factor 2a (MEF2a) and MEF2d mediated the effects of NCoR1 on cardiomyocyte hypertrophy. The receptor interaction domains (RIDs) of NCoR1 interacted with MEF2a to repress its transcriptional activity. Furthermore, NCoR1 formed a complex with MEF2a and class IIa histone deacetylases (HDACs) to suppress hypertrophy-related genes. Finally, overexpression of RIDs of NCoR1 in the heart attenuated cardiac hypertrophy and dysfunction induced by pressure overload. In conclusion, NCoR1 cooperates with MEF2 and HDACs to repress cardiac hypertrophy. Targeting NCoR1 and the MEF2/HDACs complex may be an attractive therapeutic strategy to tackle pathological cardiac hypertrophy.
© 2019 The Authors. Published under the terms of the CC BY 4.0 license.
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Hepatic IRF2BP2 Mitigates Nonalcoholic Fatty Liver Disease by Directly Repressing the Transcription of ATF3.
Hepatology2019 Sep;():. doi: 10.1002/hep.30950.
Fang Jing, Ji Yan-Xiao, Zhang Peng, Cheng Lin, Chen Yue, Chen Jun, Su Yanfang, Cheng Xu, Zhang Yan, Li Tianyu, Zhu Xuehai, Zhang Xiao-Jing, Wei Xiang,
Abstract
Although knowledge regarding the pathogenesis of nonalcoholic fatty liver disease (NAFLD) has profoundly grown in recent decade, the internal restrictive mechanisms remain largely unknown. We have recently reported that the transcription repressor interferon regulatory factor-2 binding protein 2 (IRF2BP2) is enriched in cardiomyocytes and inhibits pathological cardiac hypertrophy in mice. Notably, IRF2BP2 is abundantly expressed in hepatocytes and dramatically downregulated in steatotic livers, whereas the role of IRF2BP2 in NAFLD is unknown. Herein, using gain- and loss-of-function approaches in mice, we demonstrated that while hepatocyte-specific Irf2bp2 knockout exacerbated high-fat diet-induced hepatic steatosis, insulin resistance and inflammation, hepatic Irf2bp2 overexpression protected mice from these metabolic disorders. Moreover, the inhibitory role of IRF2BP2 on hepatosteatosis is conserved in a human hepatic cell line in vitro. Combinational analysis of digital gene expression and chromatin immunoprecipitation sequencing identified activating transcription factor 3 (ATF3) to be negatively regulated by IRF2BP2 in NAFLD. Chromatin immunoprecipitation and luciferase assay substantiated the fact that IRF2BP2 is a bona fide transcription repressor of ATF3 gene expression via binding to its promoter region. Functional studies revealed that ATF3 knockdown significantly relieved IRF2BP2 knockout-exaggerated hepatosteatosis in vitro. CONCLUSION: IRF2BP2 is an integrative restrainer in controlling hepatic steatosis, insulin resistance and inflammation in NAFLD through transcriptionally repressing ATF3 gene expression.
© 2019 by the American Association for the Study of Liver Diseases.
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Blockade of intercellular adhesion molecule-1 prevents angiotensin II-induced hypertension and vascular dysfunction.
Lab Invest2019 Sep;():. doi: 10.1038/s41374-019-0320-z.
Lang Ping-Ping, Bai Jie, Zhang Yun-Long, Yang Xiao-Lei, Xia Yun-Long, Lin Qiu-Yue, Li Hui-Hua,
Abstract
Monocyte and adhesion infiltration into the arterial subendothelium are initial steps in hypertension development. The endothelial intercellular adhesion molecule-1 (ICAM-1) has been implicated in the recruitment and adhesion of leukocytes in several cardiac diseases. However, the role of ICAM-1 in angiotensin II (Ang II)-induced hypertension development remains unknown. Hypertension was induced by administering an infusion of Ang II (1000?ng/kg/min) to wild-type (WT) mice treated with an IgG control or ICAM-1 neutralizing antibody (1 and 2?mg/mouse/day, respectively). Blood pressure was determined using the tail-cuff system. Vascular remodeling was assessed by performing a histological examination. Inflammation and reactive oxygen species (ROS) levels were determined by using immunostaining. Vascular dysfunction was assessed by aortic ring assay. The expression of fibrotic markers, cytokines and NOX was evaluated by quantitative real-time PCR analysis. Our results demonstrate that Ang II infusion markedly increased the ICAM-1 level in the aorta. Blocking ICAM-1 with a neutralizing antibody significantly attenuated Ang II-induced arterial hypertension, vascular hypertrophy, fibrosis, macrophage infiltration, and ROS production and improved vascular relaxation. In conclusion, ICAM-1-mediated monocyte adhesion and migration play a critical role in Ang II-induced arterial hypertension and vascular dysfunction. ICAM-1 inhibitors may represent a new therapeutic strategy for the treatment of this disease.
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Hexarelin protects cardiac H9C2 cells from angiotensin II-induced hypertrophy the regulation of autophagy.
Pharmazie2019 Aug;74(8):485-491. doi: 10.1691/ph.2019.9324.
Agbo E, Li M-X, Wang Y-Q, Saahene R-O, Massaro J, Tian G-Z,
Abstract
Hexarelin is a synthetic growth hormone-releasing peptide that exerts cardioprotective effects. Regulation of autophagy is known to be cardioprotective so this study examined the role of autophagy and potential regulatory mechanisms in hexarelin-elicited anti-cardiac hypertrophic action in cardiomyocytes subjected to hypertrophy. H9C2 cardiomyocytes were subjected to hypertrophy by angiotensin-II (Ang-II). Autophagic light chain-3 (LC3) and cytoskeletal proteins were determined by immunofluorescence assay. Autophagy was also detected using monodansylcadaverine (MDC) for autophagic vacuole visualization and Cyto-ID staining for autophagic flux measurement. Molecular changes were analysed by Western blotting and qRT-PCR. Apoptosis was evaluated using flow cytometry and TUNEL assay. ATP content and CCK-8 assay were used in assessing enhanced cell survival whilst oxidative stress was analysed by measuring malondialdehyde(MDA) and superoxide dismutase(SOD) levels. Ang-II induced cardiomyocyte hypertrophy, oxidative stress, apoptosis and decreased cell survival, all of which were significantly suppressed by hexarelin treatment which also enhanced autophagy in hypertrophic H9C2 cells. Furthermore, inhibition of hexarelin induced autophagy by 3-methyladenine (3MA) abolished the anti-hypertrophic function of hexarelin and also abrogated the protection of hexarelin against cell survival inhibition and apoptosis. Conversely, the application of autophagy stimulator rapamycin in H9C2 hypertrophic cells inhibited apoptosis, cell survival and reduced cell size as well. Additionally, hexarelin regulated the upstream signalling of autophagy by inhibiting the phosphorylation of mammalian target of rapamycin(mTOR). We propose that hexarelin plays a novel role of attenuating cardiomyocyte hypertrophy and apoptosis an autophagy-dependent mechanism associated with the suppression of the mTOR signalling pathway.
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Caspase-1 as Molecular Key in Cardiac Remodeling during Cardiorenal Syndrome Type 3 in the Murine Model.
Curr Mol Med2019 Sep;():. doi: 10.2174/1566524019666190916153257.
Trentin-Sonoda Mayra, Fratoni Frayli Maltoni, da Cruz Junho Carolina Victoria, Silva Wellington Caio, Panico Karine, Carneiro-Ramos Marcela Sorelli,
Abstract
BACKGROUND:
Renal ischemia/reperfusion induces a systemic inflammatory response that is directly related to the development of cardiac hypertrophy due to cardiorenal syndrome type 3. Classic inflammatory pathways have been extensively investigated in cardiovascular diseases, including the participation of inflammasome in caspase-1-dependent IL-1? cleavage.
OBJECTIVE:
In this study, we aim to understand how caspase-1 participates in cardiac remodeling induced by apoptosis.
METHODS:
Wildtype and caspase-1 knockout animals were submitted to a renal ischemia/reperfusion protocol. Briefly, left kidney ischemia was induced in male C57BL/6 mice for 60 min, followed by reperfusion for 15 days. Gene expression has been investigated by Real Time PCR. Caspase activity was also evaluated.
RESULTS:
Lack of caspase-1 was sufficient to prevent the inflammatory response and cardiac dysfunction (such as an increase of QJ interval), however, caspase-1 knockout mice subjected to the renal ischemia/reperfusion protocol still developed cardiac hypertrophy. Assessment of caspase 3/7 and 9 activity suggests that the apoptotic response observed in this model is interleukin-1?-independent. The unexpected hypertrophy can be explained by the nuclear role of caspase-1 and inactivation of the transcription factor GATA-binding factor 4.
CONCLUSION:
Our data corroborates important findings on the role of caspase-1 in the development of cardiac hypertrophy and remodeling, even in the absence of inflammation.
Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.
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Identification of inhibitors of the RGS homology domain of GRK2 by docking-based virtual screening.
Life Sci2019 Sep;():116872. doi: S0024-3205(19)30799-4.
Echeverría Emiliana, Rueda Ana Julia Velez, Cabrera Maia, Juritz Ezequiel, Burghi Valeria, Fabián Lucas, Davio Carlos, Menna Pablo Lorenzano, Fernández Natalia Cristina,
Abstract
AIMS:
G protein-coupled receptor (GPCR) kinases (GRKs) are mainly involved in the desensitization of GPCRs. Among them, GRK2 has been described to be upregulated in many pathological conditions and its crucial role in cardiac hypertrophy, hypertension, and heart failure promoted the search for pharmacological inhibitors of its activity. There have been several reports of potent and selective inhibitors of GRK2, most of them directed to the kinase domain of the protein. However, the homologous to the regulator of G protein signaling (RH) domain of GRK2 has also been shown to regulate GPCRs signaling. Herein, we searched for potential inhibitors of receptor desensitization mediated by RH domain of GRK2.
MATERIALS AND METHODS:
We performed a docking-based virtual screening utilizing the crystal structure of GRK2 to search for potential inhibitors of the interaction between GRK2 and G?q protein. To evaluate the biological activity of compounds we measured, calcium response of histamine H1 receptor (H1R) using Fura-2AM dye and H1R internalization by saturation binding experiments in A549 cells. GRK2(45-178)GFP translocation was determined in HeLa cells through confocal fluorescence imaging.
KEY FINDINGS:
We identified inhibitors of GRK2 able to reduce the RH mediated desensitization of the histamine H1 receptor and GRK2 translocation to plasma membrane. Also candidates presented adequate lipophilia and cytotoxicity profile.
SIGNIFICANCE:
We obtained compounds with the ability of reducing RH mediated actions of GRK2 that can be useful as a starting point in the development of novel drug candidates aimed to treat pathologies were GRK2 plays a key role.
Copyright © 2019. Published by Elsevier Inc.
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Automated and Interpretable Patient ECG Profiles for Disease Detection, Tracking, and Discovery.
Circ Cardiovasc Qual Outcomes2019 Sep;12(9):e005289. doi: 10.1161/CIRCOUTCOMES.118.005289.
Tison Geoffrey H, Zhang Jeffrey, Delling Francesca N, Deo Rahul C,
Abstract
BACKGROUND:
The ECG remains the most widely used diagnostic test for characterization of cardiac structure and electrical activity. We hypothesized that parallel advances in computing power, machine learning algorithms, and availability of large-scale data could substantially expand the clinical inferences derived from the ECG while at the same time preserving interpretability for medical decision-making.
METHODS AND RESULTS:
We identified 36?186 ECGs from the University of California, San Francisco database that would enable training of models for estimation of cardiac structure or function or detection of disease. We segmented the ECG into standard component waveforms and intervals using a novel combination of convolutional neural networks and hidden Markov models and evaluated this segmentation by comparing resulting electrical intervals against 141?864 measurements produced during the clinical workflow. We then built a patient-level ECG profile, a 725-element feature vector and used this profile to train and interpret machine learning models for examples of cardiac structure (left ventricular mass, left atrial volume, and mitral annulus e-prime) and disease (pulmonary arterial hypertension, hypertrophic cardiomyopathy, cardiac amyloid, and mitral valve prolapse). ECG measurements derived from the convolutional neural network-hidden Markov model segmentation agreed with clinical estimates, with median absolute deviations as a fraction of observed value of 0.6% for heart rate and 4% for QT interval. Models trained using patient-level ECG profiles enabled surprising quantitative estimates of left ventricular mass and mitral annulus e' velocity (median absolute deviation of 16% and 19%, respectively) with good discrimination for left ventricular hypertrophy and diastolic dysfunction as binary traits. Model performance using our approach for disease detection demonstrated areas under the receiver operating characteristic curve of 0.94 for pulmonary arterial hypertension, 0.91 for hypertrophic cardiomyopathy, 0.86 for cardiac amyloid, and 0.77 for mitral valve prolapse.
CONCLUSIONS:
Modern machine learning methods can extend the 12-lead ECG to quantitative applications well beyond its current uses while preserving the transparency that is so fundamental to clinical care.
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Pulmonary Artery to Left Atrium Fistula Presenting As Cardiomegaly in the Fetus: The Utility of Prenatal and Postnatal Three-Dimensional Imaging.
Circ Cardiovasc Imaging2019 Aug;12(8):e009336. doi: 10.1161/CIRCIMAGING.119.009336.
Kehr Jascha, Stirling John W, Bagnall Carol, Long Audrey, Artrip John H, Gentles Thomas L,
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Change in Physical Activity and Cardiac Structure over 10 Years: The Multi-Ethnic Study of Atherosclerosis.
Med Sci Sports Exerc2019 Oct;51(10):2033-2040. doi: 10.1249/MSS.0000000000002027.
Florido Roberta, Zhao D I, Ndumele Chiadi E, Bluemke David A, Heckbert Susan R, Allison Matthew A, Ambale-Venkatesh Bharath, Liu Chia-Ying, Lima Joao, Michos Erin D,
Abstract
INTRODUCTION:
Physical activity (PA) is inversely associated with risk of heart failure and cardiovascular disease (CVD), whereas increased left ventricular (LV) mass and mass to volume (m:v) ratio are unfavorable CVD risk factors. We assessed whether changes in leisure time PA were associated with longitudinal changes in cardiac structure in a community-based population.
METHODS:
We included 2779 Multi-Ethnic Study of Atherosclerosis participants, free of baseline CVD, who had available data on PA and cardiac magnetic resonance imaging at examinations 1 (2000-2002) and 5 (2010-2012). Physical activity was measured by a Typical Week PA Survey and converted to MET-minutes per week of moderate+vigorous activity. We used linear mixed effect models to estimate the associations of baseline and change in PA with baseline and change in cardiac structure, adjusting for CVD risk factors and body size.
RESULTS:
At baseline, the mean age was 59 yr, 53% were women, and 58% of nonwhite race/ethnicity. During average 10-yr follow-up, and after accounting for baseline PA levels, the highest quintiles of PA increase were significantly associated with increases in LV mass (2.3 g; 95% confidence interval [CI], 0.4-4.2), LV end-diastolic volume (4.7 mL; 95% CI, 2.4-7.0), and stroke volume (3.3 mL; 95% CI, 1.6-5.1), but lower M:V ratio (-2.9; 95% CI, -5.0 to -0.8) compared with the lowest quintiles. Increasing exercise PA was associated with increases in LV diameter and reductions in M:V ratio, whereas occupational PA was associated with increases in m:v ratio. Increasing PA over 10 yr was also associated with greater risk of eccentric dilated LV hypertrophy at examination 5.
CONCLUSIONS:
After accounting for baseline PA, greater positive changes in leisure-time PA levels were associated with a more eccentric-type of LV remodeling pattern over 10 yr. The clinical implications of such findings remain to be determined.
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