SOSTIENICI
Pubblicazioni recenti - cardiac hypertrophy
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Angiotensin II Mediates Cardiomyocyte Hypertrophy in Atrial Cardiomyopathy via Epigenetic Transcriptional Regulation.
Comput Math Methods Med2022 ;2022():6312100. doi: 10.1155/2022/6312100.
Zheng Liuying, Wang Jin, Zhang Rui, Zhang Yingyi, Geng Jie, Cao Lu, Zhao Xiaoyun, Geng Jianhui, Du Xinping, Hu Yuecheng, Cong Hongliang,
Abstract
Aims:
European Heart Rhythm Association established an expert consensus to define, characterize, and classify atrial cardiomyopathy into four subgroups based on their histopathological features. The predominant pathological feature of classes I and III is the hypertrophy of atrial cardiomyocytes. Here, we aim to investigate the mechanism of epigenetic transcriptional regulation of cardiomyocyte hypertrophy in atrial cardiomyopathy.
Methods and Results:
Compared with that of sinus rhythm control individuals, the myocardium of patients with atrial fibrillation exhibited increased levels of angiotensin II (AngII), chromatin-bound myocyte enhancer factor 2 (MEF2), acetylated histone H4 (H4ac), and H3K27ac; upregulation of hypertrophy-related genes; and decreased levels of histone deacetylase (HDAC) 4 and HDAC5 bound to the promoters of hypertrophy-related genes. Furthermore, incubation of atrial cardiomyocytes with AngII increased their cross-sectional area and improved the expression of hypertrophy-related genes. AngII also promoted the phosphorylation of HDAC4 and HDAC5 and induced their nuclear export. RNA sequencing analyses revealed that AngII significantly upregulated genes associated with cardiac hypertrophy. Chromatin immunoprecipitation showed that this correlated with increased levels of chromatin-bound MEF2, H4ac, and H3K27ac and decreased HDAC4 and HDAC5 enrichment in the promoters of hypertrophy-related genes. Moreover, these AngII-induced prohypertrophic effects could be partially reverted by treatment with the AngII receptor blocker losartan.
Conclusions:
AngII had a prohypertrophic effect on atrial cardiomyopathy which was epigenetic-dependent. Patients with atrial fibrillation manifest an increased susceptibility to hypertrophy and exhibit epigenetic characteristics that are permissive for the transcription of hypertrophy-related genes. AngII induces histone acetylation via the cytoplasmic-nuclear shuttling of HDACs, which constitutes a novel mechanism of atrial hypertrophy regulation and might provide a promising therapeutic strategy for atrial cardiomyopathy.
Copyright © 2022 Liuying Zheng et al.
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Targeting miR-30d reverses pathological cardiac hypertrophy.
EBioMedicine2022 Jun;81():104108. doi: S2352-3964(22)00289-4.
Li Jin, Sha Zhao, Zhu Xiaolan, Xu Wanru, Yuan Weilin, Yang Tingting, Jin Bing, Yan Yuwei, Chen Rui, Wang Siqi, Yao Jianhua, Xu Jiahong, Wang Zitong, Li Guoping, Das Saumya, Yang Liming, Xiao Junjie,
Abstract
BACKGROUND:
Pathological cardiac hypertrophy occurs in response to numerous stimuli and precedes heart failure (HF). Therapies that ameliorate pathological cardiac hypertrophy are highly needed.
METHODS:
The expression level of miR-30d was analyzed in hypertrophy models and serum of patients with chronic heart failure by qRT-PCR. Gain and loss-of-function experiments of miR-30d were performed in vitro. miR-30d gain of function were performed in vivo. Bioinformatics, western blot, luciferase assay, qRT-PCR, and immunofluorescence were performed to examine the molecular mechanisms of miR-30d.
FINDINGS:
miR-30d was decreased in both murine and neonatal rat cardiomyocytes (NRCMs) models of hypertrophy. miR-30d overexpression ameliorated phenylephrine (PE) and angiotensin II (Ang II) induced hypertrophy in NRCMs, whereas the opposite phenotype was observed when miR-30d was downregulated. Consistently, the miR-30d transgenic rat was found to protect against isoproterenol (ISO)-induced pathological hypertrophy. Mechanistically, methyltransferase EZH2 could promote H3K27me3 methylation in the promotor region of miR-30d and suppress its expression during the pathological cardiac hypertrophy. miR-30d prevented pathological cardiac hypertrophy via negatively regulating its target genes MAP4K4 and GRP78 and inhibiting pro-hypertrophic nuclear factor of activated T cells (NFAT). Adeno-associated virus (AAV) serotype 9 mediated-miR-30d overexpression exhibited beneficial effects in murine hypertrophic model. Notably, miR-30d was reduced in serum of patients with chronic heart failure and miR-30d overexpression could significantly ameliorate pathological hypertrophy in human embryonic stem cell-derived cardiomyocytes.
INTERPRETATION:
Overexpression of miR-30d may be a potential approach to treat pathological cardiac hypertrophy.
FUNDING:
This work was supported by the grants from National Key Research and Development Project (2018YFE0113500 to J Xiao), National Natural Science Foundation of China (82020108002 to J Xiao, 81900359 to J Li), the grant from Science and Technology Commission of Shanghai Municipality (20DZ2255400 and 21XD1421300 to J Xiao, 22010500200 to J Li), Shanghai Sailing Program (19YF1416400 to J Li), the "Dawn" Program of Shanghai Education Commission (19SG34 to J Xiao), the "Chen Guang" project supported by the Shanghai Municipal Education Commission and Shanghai Education Development Foundation (19CG45 to J Li).
Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.
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Riociguat attenuates left ventricular proteome and microRNA profile changes after experimental aortic stenosis in mice.
Br J Pharmacol2022 Jun;():. doi: 10.1111/bph.15910.
Benkner Alexander, Rüdebusch Julia, Nath Neetika, Hammer Elke, Grube Karina, Gross Stefan, Dhople Vishnu M, Eckstein Gertrud, Meitinger Thomas, Kaderali Lars, Völker Uwe, Fielitz Jens, Felix Stephan B,
Abstract
BACKGROUND AND PURPOSE:
Development and progression of heart failure (HF) involve endothelial and myocardial dysfunction as well as a dysregulation of the nitric oxide - soluble guanylyl cyclase - cyclic guanosine monophosphate (NO-sGC-cGMP) signalling pathway. Recently, we reported that the sGC stimulator riociguat (RIO) has beneficial effects on cardiac remodelling and progression of HF in response to chronic pressure overload. Here, we examined if these favourable RIO effects are also reflected in alterations of the myocardial proteome and microRNA profiles.
EXPERIMENTAL APPROACH:
Male C57BL/6N mice underwent transverse aortic constriction (TAC) and sham operated mice served as controls. TAC and sham animals were randomised and treated with either RIO or vehicle for five weeks, starting three weeks post-surgery when cardiac hypertrophy was established. Afterwards we performed mass spectrometric proteome analyses and microRNA sequencing of proteins and RNAs, respectively, isolated from left ventricles (LV).
KEY RESULTS:
TAC-induced changes of the LV proteome were significantly reduced by RIO treatment. Bioinformatics analyses revealed that RIO improved TAC-induced cardiovascular disease related pathways, metabolism and energy production, e.g. reversed alterations in the levels of myosin heavy chain 7 (MYH7), cardiac phospholamban (PLN), and ankyrin repeat domain-containing protein 1 (ANKRD1). RIO also attenuated TAC-induced changes of microRNA levels in the LV.
CONCLUSION AND IMPLICATIONS:
The sGC stimulator RIO has beneficial effects on cardiac structure and function during pressure overload, which is accompanied by a reversal of TAC-induced changes of the cardiac proteome and microRNA profile. Our data support the potential of RIO as a novel HF therapeutic.
This article is protected by copyright. All rights reserved.
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Bicyclol Attenuates Obesity-Induced Cardiomyopathy via Inhibiting NF-?B and MAPK Signaling Pathways.
Cardiovasc Drugs Ther2022 Jun;():. doi: 10.1007/s10557-022-07356-6.
Chen Yanghao, Lin Wante, Zhong Lingfeng, Fang Zimin, Ye Bozhi, Wang Zhe, Chattipakorn Nipon, Huang Weijian, Liang Guang, Wu Gaojun,
Abstract
PURPOSE:
Schisandra is a well-known traditional Chinese medicine in East Asia. As a traditional Chinese medicine derivative with Schisandra chinensis as raw material, bicyclol is well known for its significant anti-inflammatory effect. Chronic inflammation plays a significant part in obesity-induced cardiomyopathy. Our purpose was to explore the effect and mechanism of bicyclol on obesity-induced cardiomyopathy.
METHODS:
Mice fed with a high-fat diet (HFD) and cardiomyocytes stimulated by palmitic acid (PA) were used as models of obesity-related cardiomyopathy in vivo and in vitro, respectively. The therapeutic effect of bicyclol on pathological changes such as myocardial hypertrophy and fibrosis was evaluated by staining cardiac tissue sections. PCR was used to detect inflammatory factors in H9c2 cells and animal heart tissue after bicyclol treatment. Then, we used western blotting to detect the expression levels of the myocardial hypertrophy related protein, myocardial fibrosis related protein, NF-?B and MAPK pathways.
RESULTS:
Our results indicated that bicyclol treatment significantly alleviates HFD-induced myocardial inflammation, fibrosis, and hypertrophy by inhibiting the MAPK and NF-?B pathways. Similar to animal level results, bicyclol could significantly inhibit PA-induced inflammation and prevent NF-?B and MAPK pathways from being activated.
CONCLUSION:
Our results showed that bicyclol has potential as a drug to treat obesity-induced cardiomyopathy.
© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
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Can Blebbistatin block the hypertrophy status in the zebrafish exvivo cardiac model?
Biochim Biophys Acta Mol Basis Dis2022 Jun;():166471. doi: S0925-4439(22)00142-9.
Davide Bonvissuto, Marcello Ceci, Carol Lauri, Veronica Volpe, Roberta Bertone, Davide Cervia, Claudio Sette, Gornati Rosalba, Nicla Romano,
Abstract
Ex-vivo simple models are powered tools to study cardiac hypertrophy. It is possible to control the activation of critical genes and thus test the effects of drug therapies before the in vivo tests. A zebrafish cardiac hypertrophy developed by 500??M phenylephrine (PE) treatment in ex vivo culture has been demonstrated to activate the essential expression of the embryonal genes. These genes are the same as those described in several previous pieces of research on hypertrophic pathology in humans. The efficacy of the chemical drug Blebbistatin (BL) on hypertrophy induced ex vivo cultured hearts is studied in this research. BL can inhibit the myosins and the calcium wave in counteracting the hypertrophy status caused by PE. Samples treated with PE, BL and PE simultaneously, or pre/post-treatment with BL, have been analysed for the embryonal gene activation concerning the hypertrophy status. The qRTPCR has shown an inhibitory effect of BL treatments on the microRNAs downregulation with the consequent low expression of essential embryonal genes. In particular, BL seems to be effective in blocking the hyperplasia of the epicardium but less effective in myocardium hypertrophy. The model can make it possible to obtain knowledge on the transduction pathways activated by BL and investigate the potential use of this drug in treating cardiac hypertrophy in humans.
Copyright © 2022. Published by Elsevier B.V.
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Sex Differences in Vascular Aging and Impact of GPER Deletion.
Am J Physiol Heart Circ Physiol2022 Jun;():. doi: 10.1152/ajpheart.00238.2022.
Ogola Benard O, Abshire Caleb M, Visniauskas Bruna, Kiley Jasmine X, Horton Alec C, Clark Gabrielle L, Kilanowski-Doroh Isabella, Diaz Zaidmara, Bicego Anne N, McNally Alexandra B, Zimmerman Margaret A, Groban Leanne, Trask Aaron J, Miller Kristin S, Lindsey Sarah H,
Abstract
Aging is a nonmodifiable risk factor for cardiovascular disease associated with arterial stiffening and endothelial dysfunction. We hypothesized that sex differences exist in vascular aging processes and would be attenuated by global deletion of the G protein-coupled estrogen receptor. Blood pressure was measured by tail cuff plethysmography, pulse wave velocity (PWV) and echocardiography were assessed with high resolution ultrasound, and small vessel reactivity was measured using wire myography in adult (25 weeks) and middle-aged (57 weeks) male and female mice. Adult female mice displayed lower blood pressure and PWV, but this sex difference was absent in middle-aged mice. Aging significantly increased PWV but not blood pressure in both sexes. Adult female carotids were more distensible than males, but this sex difference was lost during aging. Acetylcholine-induced relaxation was greater in female than male mice at both ages, and only males showed aging-induced changes in cardiac hypertrophy and function. GPER deletion removed the sex difference in PWV as well as ex vivo stiffness in adult mice. The sex difference in blood pressure was absent in KO mice and was associated with endothelial dysfunction in females. These findings indicate that the impact of aging on arterial stiffening and endothelial function is not the same in male and female mice. Moreover, nongenomic estrogen signaling through GPER impacted vascular phenotype differently in male and female mice. Delineating sex differences in vascular changes during healthy aging is an important first step in improving early detection and sex-specific treatments in our aging population.
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Clinical characteristics and survival of children with hypertrophic cardiomyopathy in China: A multicentre retrospective cohort study.
EClinicalMedicine2022 Jul;49():101466. doi: 10.1016/j.eclinm.2022.101466.
Chan Wenxiu, Yang Shiwei, Wang Jian, Tong Shilu, Lin Minyin, Lu Pengtao, Yao Ruen, Wu Lanping, Chen Lijun, Guo Ying, Shen Jie, Liu Tingliang, Li Fen, Chen Huiwen, Zhang Hao, Wang Shushui, Fu Lijun,
Abstract
Background:
Few data on paediatric hypertrophic cardiomyopathy (HCM) are available in developing countries. A multicentre, retrospective, cohort study was conducted to profile the clinical characteristics and survival of children with HCM in China.
Methods:
We collected longitudinal data on children with HCM aged 0-18 years at three participating institutions between January 1, 2010 and December 31, 2019. Patients were identified by searching for the diagnosis using ICD-10 codes from the electronic medical records database. HCM was diagnosed morphologically with echocardiography or cardiovascular magnetic resonance imaging. The exclusion criteria were secondary aetiologies of myocardial hypertrophy. The primary outcomes were all-cause death or heart transplantation. The Kaplan-Meier method was used to estimate the survival rate of different groups.
Findings:
A total of 564 children were recruited, with a median age at diagnosis of 1.0 year (interquartile range, IQR: 0.4-8.0 years), followed for a median of 2.6 years (1977 patient-years, IQR:0.5, 5.9 years). The underlying aetiology was sarcomeric (382, 67.7%), inborn errors of metabolism (IEMs) (108, 19.2%), and RASopathies (74, 13.1%). A total of 149 patients (26.4%) died and no patients underwent heart transplantation during follow-up. The survival probability was 71.1% (95% confidence interval [CI], 66.3%-75.3%) at 5 years. Patients with IEMs or those diagnosed during infancy had the poorest outcomes, with an estimated 5-year survival rate of 16.9% (95% CI, 7.7%-29.1%) and 56.0% (95% CI, 48.8%-62.5%), respectively. Heart failure was the leading cause of death in the cohort (90/149, 60.4%), while sudden cardiac death was the leading cause in patients with sarcomeric HCM (32/66, 48.5%).
Interpretation:
There is a high proportion of patients with IEM and a low proportion of patients with neuromuscular disease in children with HCM in China. Overall, mortality remains high in China, especially in patients with IEMs and those diagnosed during infancy.
Funding:
National Natural Science Fund of China (81770380, 81974029), China Project of Shanghai Municipal Science and Technology Commission (20MC1920400, 21Y31900301).
© 2022 The Author(s).
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F-box and WD repeat-containing protein 7 ameliorates angiotensin II-induced myocardial hypertrophic injury via the mTOR-mediated autophagy pathway.
Exp Ther Med2022 Jul;24(1):464. doi: 10.3892/etm.2022.11391.
Liu Qiang, Han Chenjun, Wu Xiaoyun, Zhou Jian, Zang Wangfu,
Abstract
Myocardial hypertrophy is a common heart disease that is closely associated with heart failure. The expression of F-box and WD repeat-containing protein 7 (FBW7) is significantly downregulated in angiotensin (Ang) II-induced cardiac fibroblasts, suggesting that it may possess an important function in cardiac development. The present study attempted to explore the role of FBW7 in Ang II-induced myocardial hypertrophic injury and its associated mechanism of action. Reverse transcription-quantitative PCR and western blotting were used to determine the expression levels of FBW7 in Ang II-induced H9C2 cells. The expression levels of autophagy-related and mTOR signaling pathway-related proteins were detected using western blotting. Cell viability was assessed using the Cell Counting Kit-8 assay. The apoptosis rate of H9C2 cells was detected using TUNEL assay and western blotting. Cellular hypertrophy and fibrosis were assessed using phalloidin staining and western blotting. Levels of inflammatory factors were examined using ELISA and western blotting, whereas levels of oxidative stress-related markers were detected by corresponding kits. The results indicated that FBW7 expression was downregulated in Ang II-induced H9C2 cells. FBW7 upregulation enhanced the expression levels of autophagy-related proteins and activated mTOR-mediated cellular autophagy. FBW7 overexpression promoted the cell viability, inhibited Ang II-induced apoptosis, cellular hypertrophy and fibrosis in H9C2 cells via the autophagic pathway, as well as inflammation and oxidative stress. Overall, the data indicated that FBW7 overexpression ameliorated Ang II-induced hypertrophic myocardial injury via the mTOR-mediated autophagic pathway.
Copyright: © Liu et al.
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CardioNet: Automatic Semantic Segmentation to Calculate the Cardiothoracic Ratio for Cardiomegaly and Other Chest Diseases.
J Pers Med2022 Jun;12(6):. doi: 988.
Jafar Abbas, Hameed Muhammad Talha, Akram Nadeem, Waqas Umer, Kim Hyung Seok, Naqvi Rizwan Ali,
Abstract
Semantic segmentation for diagnosing chest-related diseases like cardiomegaly, emphysema, pleural effusions, and pneumothorax is a critical yet understudied tool for identifying the chest anatomy. A dangerous disease among these is cardiomegaly, in which sudden death is a high risk. An expert medical practitioner can diagnose cardiomegaly early using a chest radiograph (CXR). Cardiomegaly is a heart enlargement disease that can be analyzed by calculating the transverse cardiac diameter (TCD) and the cardiothoracic ratio (CTR). However, the manual estimation of CTR and other chest-related diseases requires much time from medical experts. Based on their anatomical semantics, artificial intelligence estimates cardiomegaly and related diseases by segmenting CXRs. Unfortunately, due to poor-quality images and variations in intensity, the automatic segmentation of the lungs and heart with CXRs is challenging. Deep learning-based methods are being used to identify the chest anatomy segmentation, but most of them only consider the lung segmentation, requiring a great deal of training. This work is based on a multiclass concatenation-based automatic semantic segmentation network, CardioNet, that was explicitly designed to perform fine segmentation using fewer parameters than a conventional deep learning scheme. Furthermore, the semantic segmentation of other chest-related diseases is diagnosed using CardioNet. CardioNet is evaluated using the JSRT dataset (Japanese Society of Radiological Technology). The JSRT dataset is publicly available and contains multiclass segmentation of the heart, lungs, and clavicle bones. In addition, our study examined lung segmentation using another publicly available dataset, Montgomery County (MC). The experimental results of the proposed CardioNet model achieved acceptable accuracy and competitive results across all datasets.
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Unexplained Left Ventricular Hypertrophy with Symptomatic High-Grade Atrioventricular Block in Elderly Patients: A Case Report.
J Clin Med2022 Jun;11(12):. doi: 3522.
Yu Tzu-Ping, Chen Ju-Yi,
Abstract
Left ventricular hypertrophy (LVH) is common among older adults. Amidst all causes, Fabry disease (FD) should be considered when LVH occurs with family history, specific clinical manifestations, or cardiac alert signs. Here, we report a case of a 76-year-old male who presented late onset concentric LVH with symptomatic high-grade atrioventricular (AV) block. After dual-chamber pacemaker implantation, interrogation revealed frequent right ventricular (RV) pacing with a wide QRS duration. The patient developed heart failure symptoms with rapid deterioration of LV systolic function. Pacing-induced cardiomyopathy (PICM) was suspected, and the pacemaker was upgraded to biventricular pacing. Further FD surveys were performed, including biochemical examinations, cardiac biopsies, and genetic sequencing, and the patient was ultimately diagnosed with a cardiac variant of FD. Particularly, we strongly suggest that physiologic pacing should be initially considered for patients with FD who have symptomatic high-grade AV block, rather than traditional RV pacing to prevent PICM.
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Derangements and Reversibility of Energy Metabolism in Failing Hearts Resulting from Volume Overload: Transcriptomics and Metabolomics Analyses.
Int J Mol Sci2022 Jun;23(12):. doi: 6809.
Tung Ying-Chang, Cheng Mei-Ling, Wu Lung-Sheng, Tang Hsiang-Yu, Huang Cheng-Yu, Chang Gwo-Jyh, Chang Chi-Jen,
Abstract
Derangements in cardiac energy metabolism have been shown to contribute to the development of heart failure (HF). This study combined transcriptomics and metabolomics analyses to characterize the changes and reversibility of cardiac energetics in a rat model of cardiac volume overload (VO) with the creation and subsequent closure of aortocaval fistula. Male Sprague-Dawley rats subjected to an aortocaval fistula surgery for 8 and 16 weeks exhibited characteristics of compensated hypertrophy (CH) and HF, respectively, in echocardiographic and hemodynamic studies. Glycolysis was downregulated and directed to the hexosamine biosynthetic pathway (HBP) and -linked-N-acetylglucosaminylation in the CH phase and was further suppressed during progression to HF. Derangements in fatty acid oxidation were not prominent until the development of HF, as indicated by the accumulation of acylcarnitines. The gene expression and intermediates of the tricarboxylic acid cycle were not significantly altered in this model. Correction of VO largely reversed the differential expression of genes involved in glycolysis, HBP, and fatty acid oxidation in CH but not in HF. Delayed correction of VO in HF resulted in incomplete recovery of defective glycolysis and fatty acid oxidation. These findings may provide insight into the development of innovative strategies to prevent or reverse metabolic derangements in VO-induced HF.
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Compound Heterozygous Variants in a Patient with Dilated Cardiomyopathy Led to an Aberrant ?-Dystroglycan Pattern.
Int J Mol Sci2022 Jun;23(12):. doi: 6685.
Gaertner Anna, Burr Lidia, Klauke Baerbel, Brodehl Andreas, Laser Kai Thorsten, Klingel Karin, Tiesmeier Jens, Schulz Uwe, Knyphausen Edzard Zu, Gummert Jan, Milting Hendrik,
Abstract
Fukutin encoded by is a ribitol 5-phosphate transferase involved in glycosylation of ?-dystroglycan. It is known that mutations in affect the glycosylation of ?-dystroglycan, leading to a dystroglycanopathy. Dystroglycanopathies are a group of syndromes with a broad clinical spectrum including dilated cardiomyopathy and muscular dystrophy. In this study, we reported the case of a patient with muscular dystrophy, early onset dilated cardiomyopathy, and elevated creatine kinase levels who was a carrier of the compound heterozygous variants p.Ser299Arg and p.Asn442Ser in . Our work showed that compound heterozygous mutations in lead to a loss of fully glycosylated ?-dystroglycan and result in cardiomyopathy and end-stage heart failure at a young age.
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Ferulic Acid, Pterostilbene, and Tyrosol Protect the Heart from ER-Stress-Induced Injury by Activating SIRT1-Dependent Deacetylation of eIF2?.
Int J Mol Sci2022 Jun;23(12):. doi: 6628.
Monceaux Kévin, Gressette Mélanie, Karoui Ahmed, Pires Da Silva Julie, Piquereau Jérôme, Ventura-Clapier Renée, Garnier Anne, Mericskay Mathias, Lemaire Christophe,
Abstract
Disturbances in Endoplasmic Reticulum (ER) homeostasis induce ER stress, which has been involved in the development and progression of various heart diseases, including arrhythmias, cardiac hypertrophy, ischemic heart diseases, dilated cardiomyopathy, and heart failure. A mild-to-moderate ER stress is considered beneficial and adaptative for heart functioning by engaging the pro-survival unfolded protein response (UPR) to restore normal ER function. By contrast, a severe or prolonged ER stress is detrimental by promoting cardiomyocyte apoptosis through hyperactivation of the UPR pathways. Previously, we have demonstrated that the NAD-dependent deacetylase SIRT1 is cardioprotective in response to severe ER stress by regulating the PERK pathway of the UPR, suggesting that activation of SIRT1 could protect against ER-stress-induced cardiac damage. The purpose of this study was to identify natural molecules able to alleviate ER stress and inhibit cardiomyocyte cell death through SIRT1 activation. Several phenolic compounds, abundant in vegetables, fruits, cereals, wine, and tea, were reported to stimulate the deacetylase activity of SIRT1. Here, we evaluated the cardioprotective effect of ten of these phenolic compounds against severe ER stress using cardiomyoblast cells and mice. Among the molecules tested, we showed that ferulic acid, pterostilbene, and tyrosol significantly protect cardiomyocytes and mice heart from cardiac alterations induced by severe ER stress. By studying the mechanisms involved, we showed that the activation of the PERK/eIF2?/ATF4/CHOP pathway of the UPR was reduced by ferulic acid, pterostilbene, and tyrosol under ER stress conditions, leading to a reduction in cardiomyocyte apoptosis. The protection afforded by these phenolic compounds was not directly related to their antioxidant activity but rather to their ability to increase SIRT1-mediated deacetylation of eIF2?. Taken together, our results suggest that ferulic acid, pterostilbene, and tyrosol are promising molecules to activate SIRT1 to protect the heart from the adverse effects of ER stress.
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SOCS3 Ablation in Leptin Receptor-Expressing Cells Causes Autonomic and Cardiac Dysfunctions in Middle-Aged Mice despite Improving Energy and Glucose Metabolism.
Int J Mol Sci2022 Jun;23(12):. doi: 6484.
Pedroso João A B, Silva Ivson B da, Zampieri Thais T, Totola Leonardo T, Moreira Thiago S, Taniguti Ana P T, Diniz Gabriela P, Barreto-Chaves Maria Luiza M, Donato Jose,
Abstract
Leptin resistance is a hallmark of obesity. Treatments aiming to improve leptin sensitivity are considered a promising therapeutical approach against obesity. However, leptin receptor (LepR) signaling also modulates several neurovegetative aspects, such as the cardiovascular system and hepatic gluconeogenesis. Thus, we investigated the long-term consequences of increased leptin sensitivity, considering the potential beneficial and deleterious effects. To generate a mouse model with increased leptin sensitivity, the suppressor of cytokine signaling 3 (SOCS3) was ablated in LepR-expressing cells (LepR mice). LepR mice displayed reduced food intake, body adiposity and weight gain, as well as improved glucose tolerance and insulin sensitivity, and were protected against aging-induced leptin resistance. Surprisingly, a very high mortality rate was observed in aging LepR mice. LepR mice showed cardiomyocyte hypertrophy, increased myocardial fibrosis and reduced cardiovascular capacity. LepR mice exhibited impaired post-ischemic cardiac functional recovery and middle-aged LepR mice showed substantial arhythmic events during the post-ischemic reperfusion period. Finally, LepR mice exhibited fasting-induced hypoglycemia and impaired counterregulatory response to glucopenia associated with reduced gluconeogenesis. In conclusion, although increased sensitivity to leptin improved the energy and glucose homeostasis of aging LepR mice, major autonomic/neurovegetative dysfunctions compromised the health and longevity of these animals. Consequently, these potentially negative aspects need to be considered in the therapies that increase leptin sensitivity chronically.
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Exploring the Potential of Symmetric Exon Deletion to Treat Non-Ischemic Dilated Cardiomyopathy by Removing Frameshift Mutations in .
Genes (Basel)2022 Jun;13(6):. doi: 1093.
Rodriguez-Polo Ignacio, Behr Rüdiger,
Abstract
Non-ischemic dilated cardiomyopathy (DCM) is one of the most frequent pathologies requiring cardiac transplants. Even though the etiology of this disease is complex, frameshift mutations in the giant sarcomeric protein Titin could explain up to 25% of the familial and 18% of the sporadic cases of DCM. Many studies have shown the potential of genome editing using CRISPR/Cas9 to correct truncating mutations in sarcomeric proteins and have established the grounds for myoediting. However, these therapies are still in an immature state, with only few studies showing an efficient treatment of cardiac diseases. This publication hypothesizes that the Titin ()-specific gene structure allows the application of myoediting approaches in a broad range of locations to reframe TTNtvvariants and to treat DCM patients. Additionally, to pave the way for the generation of efficient myoediting approaches for DCM, we screened and selected promising target locations in . We conceptually explored the deletion of symmetric exons as a therapeutic approach to restore 's reading frame in cases of frameshift mutations. We identified a set of 94 potential candidate exons of that we consider particularly suitable for this therapeutic deletion. With this study, we aim to contribute to the development of new therapies to efficiently treat titinopathies and other diseases caused by mutations in genes encoding proteins with modular structures, e.g., Obscurin.
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Cardiomyocyte Proliferation from Fetal- to Adult- and from Normal- to Hypertrophy and Failing Hearts.
Biology (Basel)2022 Jun;11(6):. doi: 880.
Bishop Sanford P, Zhang Jianyi, Ye Lei,
Abstract
The cardiomyocyte undergoes dramatic changes in structure, metabolism, and function from the early fetal stage of hyperplastic cell growth, through birth and the conversion to hypertrophic cell growth, continuing to the adult stage and responding to various forms of stress on the myocardium, often leading to myocardial failure. The fetal cell with incompletely formed sarcomeres and other cellular and extracellular components is actively undergoing mitosis, organelle dispersion, and formation of daughter cells. In the first few days of neonatal life, the heart is able to repair fully from injury, but not after conversion to hypertrophic growth. Structural and metabolic changes occur following conversion to hypertrophic growth which forms a barrier to further cardiomyocyte division, though interstitial components continue dividing to keep pace with cardiac growth. Both intra- and extracellular structural changes occur in the stressed myocardium which together with hemodynamic alterations lead to metabolic and functional alterations of myocardial failure. This review probes some of the questions regarding conditions that regulate normal and pathologic growth of the heart.
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Multidimensional Approach of Heart Failure Diagnosis and Prognostication Utilizing Cardiac Imaging with Biomarkers.
Diagnostics (Basel)2022 Jun;12(6):. doi: 1366.
Kim In-Cheol, Yoo Byung-Su,
Abstract
Heart failure (HF) is a clinical syndrome caused by various etiologies that results in systolic and diastolic cardiac dysfunction with congestion. While evaluating HF and planning for treatment, physicians utilize various laboratory tests, including electrocardiography, diverse imaging tests, exercise testing, invasive hemodynamic evaluation, or endomyocardial biopsy. Among these, cardiac imaging modalities and biomarkers are the mainstays during HF diagnosis and treatment. Recent developments in non-invasive imaging modalities, such as echocardiography, computed tomography, magnetic resonance imaging, and nuclear imaging, have helped us understand the etiology, pathophysiology, and hemodynamics of HF, and determine treatment options and predict the outcomes. Due to the convenience of their use and potential impact on HF management, biomarkers are increasingly adopted in our clinical practice as well as research purpose. Natriuretic peptide is the most widely used biomarker for the diagnosis of HF, evaluation of treatment response, and prediction of future outcomes. Other cardiac biomarkers to evaluate the pathophysiological mechanisms of HF include myocardial injury, oxidative stress, inflammation, fibrosis, hypertrophy, and neurohormonal activation. Because HF results from complex cardiac disorders, it is essential to assess the disease status multidimensionally. The proper utilization of multimodality imaging and cardiac biomarkers can improve the quality of patient management and predict clinical outcomes in HF in the era of personalized medicine.
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Role of Seipin in Human Diseases and Experimental Animal Models.
Biomolecules2022 Jun;12(6):. doi: 840.
Li Yuying, Yang Xinmin, Peng Linrui, Xia Qing, Zhang Yuwei, Huang Wei, Liu Tingting, Jia Da,
Abstract
Seipin, a protein encoded by the Berardinelli-Seip congenital lipodystrophy type 2 () gene, is famous for its key role in the biogenesis of lipid droplets and type 2 congenital generalised lipodystrophy (CGL2). gene mutations result in genetic diseases including CGL2, progressive encephalopathy with or without lipodystrophy (also called Celia's encephalopathy), and -associated motor neuron diseases. Abnormal expression of seipin has also been found in hepatic steatosis, neurodegenerative diseases, glioblastoma stroke, cardiac hypertrophy, and other diseases. In the current study, we comprehensively summarise phenotypes, underlying mechanisms, and treatment of human diseases caused by gene mutations, paralleled by animal studies including systemic or specific gene knockout, or gene overexpression. In various animal models representing diseases that are not related to mutations, differential expression patterns and functional roles of seipin are also described. Furthermore, we highlight the potential therapeutic approaches by targeting seipin or its upstream and downstream signalling pathways. Taken together, restoring adipose tissue function and targeting seipin-related pathways are effective strategies for CGL2 treatment. Meanwhile, seipin-related pathways are also considered to have potential therapeutic value in diseases that are not caused by gene mutations.
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Tumor Necrosis Factor Receptor Superfamily Member 21 Induces Endothelial-Mesenchymal Transition in Coronary Artery Endothelium of Type 2 Diabetes Mellitus.
Biomedicines2022 May;10(6):. doi: 1282.
Hsu Po-Chao, Huang Jiun-Chi, Tsai Wei-Chung, Hung Wei-Wen, Chang Wei-An, Wu Ling-Yu, Chang Chao-Yuan, Tsai Yi-Chun, Hsu Ya-Ling,
Abstract
Diabetes mellitus (DM) is an increasing threat to human health and regarded as an important public issue. Coronary artery disease is one of the main causes of death in type 2 DM patients. However, the effect of hyperglycemia on coronary artery endothelial cells (CAECs) and the pathophysiologic mechanisms are still not well-explored. This study aims to explore the signal pathway and novel biomarkers of injury of CAECs in DM in understanding the microenvironment changes and mechanisms of diabetic heart disease. Next-generation sequence (NGS) and bioinformatics analysis to analyze the CAECs of one type 2 DM patient and one normal individual was performed, and it was found that tumor necrosis factor receptor superfamily member 21 (TNFRSF21) was a soluble factor in circulating system. Further experiments confirmed that advanced glycation end products (AGEs), the metabolite derived by hyperglycemia, increased the expression of TNFRSF21 in CAECs. TNFRSF21 induced endothelial-mesenchymal transition (EndoMT) in CAECs, resulting in increased permeability of CAECs. In addition, levels of serum TNFRSF21 were higher in type 2 DM patients with left ventricular hypertrophy (LVH) than those without LVH. Serum TNFRSF21 levels were also positively correlated with the LV mass index and negatively with LV systolic function. Serum TNFRSF21 levels were associated with changes in cardiac structure and function in patients with type 2 DM. In conclusion, TNFRSF21 plays a pathogenic role in heart disease of type 2 DM, and can be used as a biomarker of the impairment of cardiac structure and function in type 2 DM patients.
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Adipocyte-Specific Expression of PGC1? Promotes Adipocyte Browning and Alleviates Obesity-Induced Metabolic Dysfunction in an HO-1-Dependent Fashion.
Antioxidants (Basel)2022 Jun;11(6):. doi: 1147.
Shen Shin-Hsueh, Singh Shailendra P, Raffaele Marco, Waldman Maayan, Hochhauser Edith, Ospino Juancarlos, Arad Michael, Peterson Stephen J,
Abstract
Recent studies suggest that PGC1-? plays a crucial role in mitochondrial and vascular function, yet the physiological significance of PGC1? and HO expression in adipose tissues in the context of obesity-linked vascular dysfunction remains unclear. We studied three groups of six-week-old C57BL/6J male mice: (1) mice fed a normal chow diet; (2) mice fed a high-fat diet (H.F.D.) for 28 weeks, and (3) mice fed a high-fat diet (H.F.D.) for 28 weeks, treated with adipose-specific overexpression of PGC-1? (transgenic-adipocyte-PGC-1?) at week 20, and continued on H.F.D. for weeks 20-28. R.N.A. arrays examined 88 genes involved in adipocyte proliferation and maturation. Blood pressure, tissue fibrosis, fasting glucose, and oxygen consumption were measured, as well as liver steatosis, and the expression levels of metabolic and mitochondrial markers. Obese mice exhibited a marked reduction of PGC1? and developed adipocyte hypertrophy, fibrosis, hepatic steatosis, and decreased mitochondrial respiration. Mice with adipose-specific overexpression of PGC1-? exhibited improvement in HO-1, mitochondrial biogenesis and respiration, with a decrease in fasting glucose, reduced blood pressure and fibrosis, and increased oxygen consumption. PGC-1? led to the upregulated expression of processes associated with the browning of fat tissue, including UCP1, FGF21, and pAMPK signaling, with a reduction in inflammatory adipokines, NOV/CCN3 expression, and TGF?. These changes required HO-1 expression. The R.N.A. array analysis identified subgroups of genes positively correlated with contributions to the browning of adipose tissue, all dependent on HO-1. Our observations reveal a positive impact of adipose-PGC1-? on distal organ systems, with beneficial effects on HO-1 levels, reversing obesity-linked cardiometabolic disturbances.
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