Development Of Cardiac Remodeling Research Articles

PiRNA in Cardiovascular Disease: Focus on Cardiac Remodeling and Cardiac Protection.

Cardiovascular diseases (CVDs) are common causes of death, which take about 18.6 million lives worldwide every year. Currently, exploring strategies that delay ventricular remodeling, reduce cardiomyocyte death, and promote cardiomyocyte regeneration has been the hotspot and difficulty of the ischemic heart disease (IHD) research field. Previous studies indicate that piwi-interacting RNA (piRNA) plays a vital role in the occurrence and development of cardiac remodeling and may offer novel therapeutic strategies for cardiac repair. The best-known biological function of piRNA is to silence transposons in cells. In the cardiovascular system, piRNA is known to participate in cardiac progenitor cell proliferation, AKT pathway regulation, and cardiac remodeling and decompensation. In this review, we systematically discuss the research progress on piRNA in CVDs, especially the mechanism of cardiac remodeling and the potential functions in cardiac protection, which provides new insights for the progress and treatment of cardiovascular diseases. Piwi-interacting RNA (piRNA) is one of the noncoding RNAs, with the best -known biological function to silence transposons in cells. Now piRNA is found to participate in cardiac progenitor cell proliferation, AKT pathway regulation, cardiac remodeling and decompensation, which implies the potential of piRNA in the diagnosis and treatment of cardiovascular diseases. Over expression of piRNA could promote cardiac apoptosis and cardiac hypertrophy, thus targeted therapy which inhibits expression of associated piRNA may reduce cardiac remodeling and reduce inflammation caused by necrotic cardiomyocytes. PiRNA is also speculated to participate in the proliferation of cardiac progenitor cells, implying the potential to induce cardiac regeneration th erapy, which provides new insights for treatment of cardiovascular diseases. At present, the treatment strategy of cardiac remodeling emphasizes the control of risk factors, prevention of disease progression and individualized treatment. With further studies in mechanism of piRNA, potential therapies above may come true and more therapies in cardiovascular diseases may be found.

Changes in gut microbiota linked to a prevention of cardiac remodeling induced by hypertension in spontaneously hypertensive rats fed a pawpaw fruit diet

ObjectiveDietary intake of fruit is associated with lower incidence of hypertension and cardiovascular risk. Papaya is a kind of delicious fruit and reported has dietary therapeutic effects, such as digestive stimulation and hypotensive efficacy. However, the mechanism of pawpaw involved have not been elucidated. Here, we illustrate that the effect of pawpaw on the gut microbiota and the prevention of cardiac remodeling. MethodsGut microbiome, cardiac structure/function, and blood pressure were examined in SHR and WKY groups. The intestinal barrier was tested with histopathologic; immunostaining and Western blot were used to measure the tight junction protein level; Gpr41 was tested by RT-PCR, and inflammatory factors were detected with ELISA. ResultsWe observed a significant decrease in microbial richness, diversity, and evenness is the spontaneously hypertensive rat (SHR), in addition to an increased Firmicutes/Bacteroidetes (F/B) ratio. These changes were accompanied by decreased in acetate and butyrate-producing bacteria. Compared with SHR, treatment with pawpaw at the dosage of 10 g/kg for 12 weeks significantly reduced the blood pressure, cardiac fibrosis and cardiac hypertrophy, while the ratio of F/B decreased. We also found that the concentration of short-chain fatty acids (SCFAs) was increased in SHR fed with pawpaw compared with that in control group, while the gut barrier was restored and level of proinflammatory cytokines in the serum were decreased. ConclusionsPawpaw, rich of high fiber, led to changes in the gut microbiota that played a protective role in the development of cardiac remodeling. The potential mechanism of pawpaw may explained by the generation of one of the main metabolites of the gut microbiota, the short-chain fatty acid acetate, increasing tight junction protein level occluding to enhance the gut barrier for less releasing the inflammation cytokines, and upregulating G-protein-coupled receptor 41 (GPR41) to reduce blood pressure.

Morphological and Functional Remodeling of the Ischemic Heart Correlates with Homocysteine Levels.

Homocysteine (Hcy) is involved in various methylation processes, and its plasma level is increased in cardiac ischemia. Thus, we hypothesized that levels of homocysteine correlate with the morphological and functional remodeling of ischemic hearts. Thus, we aimed to measure the Hcy levels in the plasma and pericardial fluid (PF) and correlate them with morphological and functional changes in the ischemic hearts of humans. Concentration of total homocysteine (tHcy) and cardiac troponin-I (cTn-I) of plasma and PF were measured in patients undergoing coronary artery bypass graft (CABG) surgery (n = 14). Left-ventricular (LV) end-diastolic diameter (LVED), LV end-systolic diameter (LVES), right atrial, left atrial (LA) area, thickness of interventricular septum (IVS) and posterior wall, LV ejection fraction (LVEF), and right ventricular outflow tract end-diastolic area (RVOT EDA) of CABG and non-cardiac patients (NCP; n = 10) were determined by echocardiography, and LV mass was calculated (cLVM). Positive correlations were found between Hcy levels of plasma and PF, tHcy levels and LVED, LVES and LA, and an inverse correlation was found between tHcy levels and LVEF. cLVM, IVS, and RVOT EDA were higher in CABG with elevated tHcy (>12 µM/L) compared to NCP. In addition, we found a higher cTn-I level in the PF compared to the plasma of CABG patients (0.08 ± 0.02 vs. 0.01 ± 0.003 ng/mL, p < 0.001), which was ~10 fold higher than the normal level. We propose that homocysteine is an important cardiac biomarker and may have an important role in the development of cardiac remodeling and dysfunction in chronic myocardial ischemia in humans.

Mechanism of histone deacetylases in cardiac hypertrophy and its therapeutic inhibitors.

Cardiac hypertrophy is a key process in cardiac remodeling development, leading to ventricle enlargement and heart failure. Recently, studies show the complicated relation between cardiac hypertrophy and epigenetic modification. Post-translational modification of histone is an essential part of epigenetic modification, which is relevant to multiple cardiac diseases, especially in cardiac hypertrophy. There is a group of enzymes related in the balance of histone acetylation/deacetylation, which is defined as histone acetyltransferase (HAT) and histone deacetylase (HDAC). In this review, we introduce an important enzyme family HDAC, a key regulator in histone deacetylation. In cardiac hypertrophy HDAC I downregulates the anti-hypertrophy gene expression, including Kruppel-like factor 4 (Klf4) and inositol-5 phosphatase f (Inpp5f), and promote the development of cardiac hypertrophy. On the contrary, HDAC II binds to myocyte-specific enhancer factor 2 (MEF2), inhibit the assemble ability to HAT and protect against cardiac hypertrophy. Under adverse stimuli such as pressure overload and calcineurin stimulation, the HDAC II transfer to cytoplasm, and MEF2 can bind to nuclear factor of activated T cells (NFAT) or GATA binding protein 4 (GATA4), mediating inappropriate gene expression. HDAC III, also known as SIRTs, can interact not only to transcription factors, but also exist interaction mechanisms to other HDACs, such as HDAC IIa. We also present the latest progress of HDAC inhibitors (HDACi), as a potential treatment target in cardiac hypertrophy.

Diagnosis, clustering, and immune cell infiltration analysis of m6A-related genes in patients with acute myocardial infarction-a bioinformatics analysis.

BackgroundAccurate myocardial infarction (AMI) is one of the leading causes of mortality worldwide. N6-methyladenosine (m6A) modification plays an important role in the development of cardiac remodeling and the cardiomyocyte contractile function. The aim of this study is to analyze the m6A-related molecular biological mechanisms of AMI in terms of accurate diagnosis and prognosis.MethodsThe platform data and probe data of the GSE66360 data set were downloaded. The differential analysis was conducted by combining the m6A-related gene expression. Thereafter, a diagnostic model was established using the random-forest method. The diagnostic accuracy of the diagnostic models was assessed by using the area under the receiver operating characteristic (ROC) curve (AUC). Next, the patients with AMI were clustered by unsupervised machine learning using the R software. Finally, an immune cell clustering analysis for each cluster was conducted to determine the correlations between m6A-related gene expression and the infiltration amount of the immune cells. The case and control groups were not matched in terms of demographics.ResultsThe GSE6636 data set comprised 99 participants (49 patients with AMI and 50 without in control group). The differential analysis identified 10 m6A-related genes: 5 writers [Methyltransferase-like 3 (METTL3), Methyltransferase-like 14 (METTL14), Wilms tumor 1-associated protein (WTAP), Zinc Finger CCCH-Type Containing 13 (ZC3H13), and Casitas B-lineage proto-oncogene like 1 (CBLL1)], 4 readers [YT521-B homology domain-containing family 3 (YTHDF3), Fragile X mental retardation type 1 (FMR1), YT521-B homology-domain-containing protein 1 (YTHDC1), and insulin-like growth factor binding protein 3 (IGFBP3)] and 1 eraser [fat mass and obesity associated (FTO) gene]. The Mean Decrease Gini (MDG) values of these 10 genes were greater than 2. The FTO, WTAP, YTHDC1, IGFBP3, and CBLL1 were included in the model with a C index of 0.842. METTL3, ZC3H13, WTAP, and CBLL1 were highly expressed in Type A, and YTHDF3 was highly expressed in Type B.ConclusionsA diagnostic model of AMI was established based on the genes of FTO, WTAP, YTHDC1, IGFBP3, and CBLL1. Additionally, 2 molecular subtypes were successfully identified from the above-mentioned gene. Our findings could provide a novel method for the accurate diagnosis of AMI.

Angiotensin II Induces Cardiac Edema and Hypertrophic Remodeling through Lymphatic-Dependent Mechanisms.

Cardiac lymphatic vessel growth (lymphangiogenesis) and integrity play an essential role in maintaining tissue fluid balance. Inhibition of lymphatic lymphangiogenesis is involved in cardiac edema and cardiac remodeling after ischemic injury or pressure overload. However, whether lymphatic vessel integrity is disrupted during angiotensin II- (Ang II-) induced cardiac remodeling remains to be investigated. In this study, cardiac remodeling models were established by Ang II (1000 ng/kg/min) in VEGFR-3 knockdown (Lyve-1Cre VEGFR-3f/−) and wild-type (VEGFR-3f/f) littermates. Our results indicated that Ang II infusion not only induced cardiac lymphangiogenesis and upregulation of VEGF-C and VEGFR-3 expression in the time-dependent manner but also enhanced proteasome activity, MKP5 and VE-cadherin degradation, p38 MAPK activation, and lymphatic vessel hyperpermeability. Moreover, VEGFR-3 knockdown significantly inhibited cardiac lymphangiogenesis in mice, resulting in exacerbation of tissue edema, hypertrophy, fibrosis superoxide production, inflammation, and heart failure (HF). Conversely, administration of epoxomicin (a selective proteasome inhibitor) markedly mitigated Ang II-induced cardiac edema, remodeling, and dysfunction; upregulated MKP5 and VE-cadherin expression; inactivated p38 MAPK; and reduced lymphatic vessel hyperpermeability in WT mice, indicating that inhibition of proteasome activity is required to maintain lymphatic endothelial cell (LEC) integrity. Our results show that both cardiac lymphangiogenesis and lymphatic barrier hyperpermeability are implicated in Ang II-induced adaptive hypertrophic remodeling and dysfunction. Proteasome-mediated hyperpermeability of LEC junctions plays a predominant role in the development of cardiac remodeling. Selective stimulation of lymphangiogenesis or inhibition of proteasome activity may be a potential therapeutic option for treating hypertension-induced cardiac remodeling.

Comprehensive Analysis of N6-Methyladenosine RNA Methylation Regulators Expression Identify Distinct Molecular Subtypes of Myocardial Infarction.

Background: Myocardial infarction (MI) is one of the leading threats to human health. N6-methyladenosine (m6A) modification, as a pivotal regulator of messenger RNA stability, protein expression, and cellular processes, exhibits important roles in the development of cardiac remodeling and cardiomyocyte contractile function.Methods: The expression levels of m6A regulators were analyzed using the GSE5406 database. We analyzed genome-wide association study data and single-cell sequencing data to confirm the functional importance of m6A regulators in MI. Three molecular subtypes with different clinical characteristics were established to tailor treatment strategies for patients with MI. We applied pathway analysis and differentially expressed gene (DEG) analysis to study the changes in gene expression and identified four common DEGs. Furthermore, we constructed the protein–protein interaction network and confirmed several hub genes in three clusters of MI. To lucubrate the potential functions, we performed a ClueGO analysis of these hub networks.Results: In this study, we identified that the levels of FTO, YTHDF3, ZC3H13, and WTAP were dramatically differently expressed in MI tissues compared with controls. Bioinformatics analysis showed that DEGs in MI were significantly related to modulating calcium signaling and chemokine signaling, and m6A regulators were related to regulating glucose measurement and elevated blood glucose levels. Furthermore, genome-wide association study data analysis showed that WTAP single-nucleotide polymorphism was significantly related to the progression of MI. In addition, single-cell sequencing found that WTAP is widely expressed in the heart tissues. Moreover, we conducted consensus clustering for MI in view of the dysregulated m6A regulators’ expression in MI. According to the expression levels, we found MI patients could be clustered into three subtypes. Pathway analysis showed the DEGs among different clusters in MI were assigned to HIF-1, IL-17, MAPK, PI3K-Akt signaling pathways, etc. The module analysis detected several genes, including BAG2, BAG3, MMP2, etc. We also found that MI-related network was significantly related to positive and negative regulation of angiogenesis and response to heat. The hub networks in MI clusters were significantly related to antigen processing and ubiquitin-mediated proteolysis, RNA splicing, and stability, indicating that these processes may contribute to the development of MI.Conclusion: Collectively, our study could provide more information for understanding the roles of m6A in MI, which may provide a novel insight into identifying biomarkers for MI treatment and diagnosis.

Urotensin II induces activation of NLRP3 and pyroptosis through calcineurin in cardiomyocytes

Cell pyroptosis, a new type of programmed cell death, has been recently reported to play important roles in the development of cardiac remodeling. How cardiomyocyte pyroptosis is induced remains to be elucidated. Urotensin II (UII) has been known closely related to cardiac remodeling and the development of heart failure. Inhibition of UII receptors has been shown to be effective in the treatment of cardiac hypertrophy and remodeling. However, it is not clear whether UII might induce cardiomyocyte pyroptosis. We here examined the effect of UII treatment on pyroptosis in cultured cardiomyocytes. Treatment of cardiomyocyes of neonatal rats with UII (500 nmol/l) for 48 hours induced a significant pyroptosis as evidenced by not only increased cell death but also upregulated expression levels of NLR family pyrin domain containing 3 (NLRP3), caspase-1, IL-1β, IL-18 and gasdermin D (GMDSD)-N which are important markers for the identification of cell pyroptosis. All these pyroptosis responses induced by UII were abrogated by an inhibitor of NLRP3. Moreover, the antagonist of UII receptor, Urantide abolished UII- induced cardiomyocyte pyroptosis. Additionally, inhibition of calcineurin by cyclosporin A rather than that of CaMKII by KN93 suppressed the UII-upregulated expression levels of those pyroptosis markers. We therefore demonstrate that UII might induce cardiomyocyte pyroptosis through calcineurin.

Lutein attenuates angiotensin II- induced cardiac remodeling by inhibiting AP-1/IL-11 signaling

RationaleOxidative stress plays a critical role in the development of cardiac remodeling and heart failure. Lutein, the predominant nonvitamin A carotenoid, has been shown to have profound effects on oxidative stress. However, the effect of lutein on angiotensin II (Ang II)-induced cardiac remodeling and heart failure remains unknown. ObjectiveThe aim of this study was to determine whether lutein is involved in cardiac remodeling and to elucidate the underlying molecular mechanisms. Methods and resultsIn vitro experiments with isolated neonatal rat cardiomyocytes (NRCMs) and cardiac fibroblasts (CFs) revealed that lutein significantly attenuated Ang II-induced collagen expression in CFs, and cardiomyocyte hypertrophy. The Ang II-induced increases in superoxide generation, inflammation and apoptosis in cultured CFs were strikingly prevented by lutein. In vivo, fibrosis, hypertrophic cardiomyocyte and superoxide generation were analyzed, and lutein was demonstrated to confer resistance to Ang II-induced cardiac remodeling in mice. Mechanistically, RNA sequencing revealed that interleukin-11 (IL-11) expression was significantly upregulated in mouse hearts in response to Ang II infusion and was significantly suppressed in the hearts of lutein-treated mice. Furthermore, IL-11 overexpression blocked the effects of lutein on fibrosis and oxidative stress in CFs and impaired the protective effect of lutein on cardiac remodeling. Notably, we discovered that lutein could reduce Ang II-induced IL-11 expression, at least partly through the regulation of activator protein (AP)-1 expression and activity. ConclusionsLutein has potential as a treatment for cardiac remodeling and heart failure via the suppression of IL-11 expression.

Clinical assessment of endothelial function in heart failure with preserved ejection fraction: A meta-analysis with meta-regressions.

Endothelial dysfunction is a key mechanism in the development of cardiac remodelling and diastolic dysfunction in heart failure with preserved ejection fraction (HFpEF). Flow-mediated (FMD) and nitrate-mediated dilation (NMD) are noninvasive methods to assess endothelial function. We performed a meta-analysis evaluating the impact of HFpEF on FMD and NMD. PubMed, Web of Science, Scopus and EMBASE databases were systematically searched according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Differences were expressed as mean difference (MD) with 95% confidence intervals (95%CI). The random effects method was used. A total of seven studies were included in the final analysis, 7 with data on FMD (326 HFpEF patients and 417 controls) and 3 on NMD (185 HFpEF patients and 271 controls). Compared to controls, HFpEF patients showed significantly lower FMD (MD: -1.929; 95%CI: -2.770, -1.088; P<.0001) and NMD values (MD: -2.795; 95%CI: -3.876, -1.715; P<.0001). Sensitivity analyses substantially confirmed results. Meta-regression models showed that increasing differences in E/A ratio (Z-score: -2.002; P=.045), E/E' ratio (Z-score: -2.181; P=.029) and left atrial diameter (Z-score: -1.951; P=.050) were linked to higher differences in FMD values between cases and controls. Impaired endothelial function can be documented in HFpEF, with the possibility of a direct association between the severity of diastolic and endothelial dysfunction. Targeting endothelial dysfunction through pharmacological and rehabilitation strategies may represent an attractive therapeutic option.

Suppression of Cardiac Sympathetic Ganglion Attenuates Cardiac Remodeling in a Circadian Disruption Model

Background: Circadian rhythms have a considerable impact on the daily physiology of the heart, and their disruption causes pathology. Sympathetic nervous system is essential for transmitting circadian information from central clock to peripheral organs. The role of cardiac sympathetic ganglion, a key target of cardiac sympathetic outflow, in circadian disruption-related cardiovascular diseases is not completely understood. Thereby, we aim todiscuss whether cardiac sympathetic ganglion plays an important role in the development of cardiac remodeling after myocardial infarction (MI)in a circadian disruption model. Methods: Rats were randomly divided into three groups: Sham group (Sham), MI group (MI), and MI+ circadian disruption group (MI+Dis); rats were treated with PRV injections for trans-synaptic retrograde tracing; rats were randomly divided into two groups: MI+ circadian disruption+ Empty Vector+ CNO (Empty Vector) and MI+ circadian disruption+ hM4D(Gi)+ CNO (hM4D(Gi)). Findings: Circadian disruption significantly facilitated cardiac remodeling after MI with lower systolic function, larger left ventricular volume, increased infarct size and aggravated cardiac fibrosis. Serum norepinephrine levels and cardiac sympathetic remodeling makers were also significantly increased by disruption. PRV virus-labeled neurons were identified in the SCG, PVN, and SCN regions. Ganglionic blockade via DREADD technique suppressed the cardiac sympathetic outflow and significantly alleviated the disruption-related cardiac dysfunction. Interpretation: Circadian disruption adversely affected cardiac remodeling after MI, possibly by increasing the cardiac sympathetic outflow, and cardiac sympathetic ganglionic blockade canattenuatethis disruption-related cardiac dysfunction. Funding Statement: National Key R&D Program of China, and National Natural Science Foundation of China. Declaration of Interests: None. Ethics Approval Statement: Experimental protocols were conducted under the guidelines of the National Institutes of Health and were approved by the Animal Care and Use Committees of Renmin Hospital of Wuhan University.

TRIF/EGFR signalling mediates angiotensin-II-induced cardiac remodelling in mice.

The excessive activation of renin-angiotensin system (RAS) is one of key pathophysiological characteristics in the development of cardiac remodelling. Angiotensin (Ang) II, as a main active peptide in RAS, induces cardiac structural disorders and dysfunction. However, the molecular mechanisms are still not fully disclosed. Present study aimed to determine the role and potential mechanisms of cardiac TIR-domain-containing adapter-inducing interferon-β (TRIF) in Ang-II-mediated cardiac remodelling in mice. In vitro and in vivo studies showed Ang II and downstream aldosterone obviously increased the expression of TRIF, accompanied with cardiac structural abnormalities and functional injuries. Specific blockage of cardiac TRIF effectively decreased Ang-II/aldosterone-induced cardiac inflammation, fibrosis, hypertrophy and dysfunction in mice. Mechanistically, the TRIF triggered the activation of EGF receptor (EGFR) signalling by nuclear factor (NF)-κB transcriptional regulation and downstream EGFR ligands. Taken together, present study supported that cardiac TRIF was a potential therapeutic target for attenuating cardiac pathophysiological remodelling. The TRIF/EGFR axis partially explained the molecular mechanism of Ang-II/aldosterone-induced cardiac inflammation, fibrosis, hypertrophy and dysfunction in mice.

Transcriptional signatures regulated by TRPC1/C4-mediated Background Ca2+ entry after pressure-overload induced cardiac remodelling

AimsAfter summarizing current concepts for the role of TRPC cation channels in cardiac cells and in processes triggered by mechanical stimuli arising e.g. during pressure overload, we analysed the role of TRPC1 and TRPC4 for background Ca2+ entry (BGCE) and for cardiac pressure overload induced transcriptional remodelling. Methods and resultsMn2+-quench analysis in cardiomyocytes from several Trpc-deficient mice revealed that both TRPC1 and TRPC4 are required for BGCE. Electrically-evoked cell shortening of cardiomyocytes from TRPC1/C4-DKO mice was reduced, whereas parameters of cardiac contractility and relaxation assessed in vivo were unaltered. As pathological cardiac remodelling in mice depends on their genetic background, and the development of cardiac remodelling was found to be reduced in TRPC1/C4-DKO mice on a mixed genetic background, we studied TRPC1/C4-DKO mice on a C57BL6/N genetic background. Cardiac hypertrophy was reduced in those mice after chronic isoproterenol infusion (−51.4%) or after one week of transverse aortic constriction (TAC; −73.0%). This last manoeuvre was preceded by changes in the pressure overload induced transcriptional program as analysed by RNA sequencing. Genes encoding specific collagens, the Mef2 target myomaxin and the gene encoding the mechanosensitive channel Piezo2 were up-regulated after TAC in wild type but not in TRPC1/C4-DKO hearts. ConclusionsDeletion of the TRPC1 and TRPC4 channel proteins protects against development of pathological cardiac hypertrophy independently of the genetic background. To determine if the TRPC1/C4-dependent changes in the pressure overload induced alterations in the transcriptional program causally contribute to cardio-protection needs to be elaborated in future studies.

In-depth proteomics approach reveals novel biomarkers of cardiac remodelling after myocardial infarction: An exploratory analysis.

Cardiac remodelling following myocardial infarction (MI) is a maladaptive change associated with progressive heart failure and compromises long‐term clinical outcome. A substantial proportion of patients afflicted by MI still develop adverse outcomes associated with cardiac remodelling. Therefore, it is crucial to identify biomarkers for the early prediction of cardiac remodelling. An in‐depth proteomics approach, including both semi‐quantitative and quantitative antibody arrays, was used to identify circulating biomarkers that may be associated with detrimental cardiac remodelling. Furthermore, statistical correlation analysis was performed between the candidate biomarkers and clinical cardiac remodelling data to demonstrate their clinical utility. A systematic proteomics approach revealed that sclerostin (SOST), growth differentiation factor‐15 (GDF‐15), urokinase‐type plasminogen activator (uPA), and midkine (MK) were increased, while monocyte chemotactic protein‐3 (MCP‐3) was uniquely decreased in MI patients who developed cardiac remodelling, compared to MI patients who did not develop cardiac remodelling and healthy humen. Moreover, correlation analyses between serum proteomes and cardiac remodelling echocardiographic parameters demonstrated a moderate positive association between left ventricular end‐diastolic volume index (LVEDVi) and the three serum proteins, uPA, MK and GDF‐15 (P < .05, respectively), and a moderate negative correlation between LV ejection fraction (LVEF) and these serum proteins (P < .05, respectively). Importantly, uPA and MK were firstly identified to be associated with the development of cardiac remodelling. The present study contributes to a better understanding of the various cytokines expressed during adverse cardiac remodelling. The identified biomarkers may facilitate early identification of patients at high risk of ischaemic heart failure pending further confirmation through larger clinical trials.

Tongmai Yangxin intervening in myocardial remodeling after PCI for coronary heart disease: study protocol for a double-blind, randomized controlled trial

BackgroundCoronary heart disease (CHD) has become a common cardiovascular disease that seriously threatens the health of people. As reperfusion in the early phase and drug therapy, especially percutaneous coronary intervention (PCI), have become widely used in the clinic, the mortality of acute myocardial infarction in the short term has been reduced significantly. In addition, in 40%–56% of patients who experience myocardial infarction, cardiac dysfunction occurs and about 25%–33% develop heart failure.MethodsThis study was designed as a multicenter, double-blind, randomized, placebo-controlled, parallel-group, superiority trial. Participants were randomly assigned in a 1:1 ratio through a centrally controlled, computer-generated, simple randomization schedule. The primary outcome was left ventricular end-diastolic volume index = left ventricular end-diastolic volume/body surface area. The combined secondary outcomes include traditional Chinese medicine syndrome score, echocardiogram results, 6-minute walk test results, Seattle Angina Questionnaire score, cardiac magnetic resonance imaging results, biological indicators, dynamic electrocardiogram results, and experiment event rate. Assessments will be performed at baseline and at 4, 8, and 12 weeks after randomization.DiscussionThis trial will demonstrate that the addition of a Tongmai Yangxin pill (TMYX) to conventional treatment will intervene in the development of cardiac remodeling and cardiac dysfunction.Trial registrationThis study was registered in the Chinese Clinical Trial Registry on 7 May 2019. The registration number is ChiCRT1900023023 (http://www.chictr.org.cn/showproj.aspx?proj=12370).

The Roles of Noncardiomyocytes in Cardiac Remodeling.

Cardiac remodeling is a common characteristic of almost all forms of heart disease, including cardiac infarction, valvular diseases, hypertension, arrhythmia, dilated cardiomyopathy and other conditions. It is not merely a simple outcome induced by an increase in the workload of cardiomyocytes (CMs). The remodeling process is accompanied by abnormalities of cardiac structure as well as disturbance of cardiac function, and emerging evidence suggests that a wide range of cells in the heart participate in the initiation and development of cardiac remodeling. Other than CMs, there are numerous noncardiomyocytes (non-CMs) that regulate the process of cardiac remodeling, such as cardiac fibroblasts and immune cells (including macrophages, lymphocytes, neutrophils, and mast cells). In this review, we summarize recent knowledge regarding the definition and significant effects of various non-CMs in the pathogenesis of cardiac remodeling, with a particular emphasis on the involved signaling mechanisms. In addition, we discuss the properties of non-CMs, which serve as targets of many cardiovascular drugs that reduce adverse cardiac remodeling.

Cardioprotective effects of α-cardiac actin on oxidative stress in a dilated cardiomyopathy mouse model.

The expression of α-cardiac actin, a major constituent of the cytoskeleton of cardiomyocytes, is dramatically decreased in a mouse model of dilated cardiomyopathy triggered by inducible cardiac-specific serum response factor (Srf) gene disruption that could mimic some forms of human dilated cardiomyopathy. To investigate the consequences of the maintenance of α-cardiac actin expression in this model, we developed a new transgenic mouse based on Cre/LoxP strategy, allowing together the induction of SRF loss and a compensatory expression of α-cardiac actin. Here, we report that maintenance of α-cardiac actin within cardiomyocytes temporally preserved cytoarchitecture from adverse cardiac remodeling through a positive impact on both structural and transcriptional levels. These protective effects were accompanied in vivo by the decrease of ROS generation and protein carbonylation and the downregulation of NADPH oxidases NOX2 and NOX4. We also show that ectopic expression of α-cardiac actin protects HEK293 cells against oxidative stress induced by H2 O2 . Oxidative stress plays an important role in the development of cardiac remodeling and contributes also to the pathogenesis of heart failure. Taken together, these findings indicate that α-cardiac actin could be involved in the regulation of oxidative stress that is a leading cause of adverse remodeling during dilated cardiomyopathy development.

Cardiomyocyte Sirt (Sirtuin) 7 Ameliorates Stress-Induced Cardiac Hypertrophy by Interacting With and Deacetylating GATA4.

Sirt (Sirtuin) 7, the most recently identified mammalian sirtuin, has been shown to contribute to appropriate wound healing processes after acute cardiovascular insult. However, its role in the development of cardiac remodeling after pressure overload is unclear. Cardiomyocyte-specific Sirt7-knockout and control mice were subjected to pressure overload induced by transverse aortic constriction. Cardiac hypertrophy and functions were then examined in these mice. Sirt7 protein expression was increased in myocardial tissue after pressure overload. Transverse aortic constriction-induced increases in heart weight/tibial length were significantly augmented in cardiomyocyte-specific Sirt7-knockout mice compared with those of control mice. Histological analysis showed that the cardiomyocyte cross-sectional area and fibrosis area were significantly larger in cardiomyocyte-specific Sirt7-deficient mice. Cardiac contractile functions were markedly decreased in cardiomyocyte-specific Sirt7-deficient mice. Mechanistically, we found that Sirt7 interacted directly with GATA4 and that the exacerbation of phenylephrine-induced cardiac hypertrophy by Sirt7 knockdown was decreased by GATA4 knockdown. Sirt7 deacetylated GATA4 in cardiomyocytes and regulated its transcriptional activity. Interestingly, we demonstrated that treatment with nicotinamide mononucleotide, a known key NAD+ intermediate, ameliorated agonist-induced cardiac hypertrophies in a Sirt7-dependent manner in vitro. Sirt7 deficiency in cardiomyocytes promotes cardiomyocyte hypertrophy in response to pressure overload. Sirt7 exerts its antihypertrophic effect by interacting with and promoting deacetylation of GATA4.

MiR-154-5p Functions as an Important Regulator of Angiotensin II-Mediated Heart Remodeling.

Chronic hypertension, valvular heart disease, and heart infarction cause cardiac remodeling and potentially lead to a series of pathological and structural changes in the left ventricular myocardium and a progressive decrease in heart function. Angiotensin II (AngII) plays a key role in the onset and development of cardiac remodeling. Many microRNAs (miRNAs), including miR-154-5p, may be involved in the development of cardiac remolding, but the underlying molecular mechanisms remain unclear. We aimed to characterize the function of miR-154-5p and reveal its mechanisms in cardiac remodeling induced by AngII. First, angiotensin II led to concurrent increases in miR-154-5p expression and cardiac remodeling in adult C57BL/6J mice. Second, overexpression of miR-154-5p to a level similar to that induced by AngII was sufficient to trigger cardiomyocyte hypertrophy and apoptosis, which is associated with profound activation of oxidative stress and inflammation. Treatment with a miR-154-5p inhibitor noticeably reversed these changes. Third, miR-154-5p directly inhibited arylsulfatase B (Arsb) expression by interacting with its 3′-UTR and promoted cardiomyocyte hypertrophy and apoptosis. Lastly, the angiotensin type 1 receptor blocker telmisartan attenuated AngII-induced cardiac hypertrophy, apoptosis, and fibrosis by blocking the increase in miR-154-5p expression. Moreover, upon miR-154-5p overexpression in isolated cardiomyocytes, the protective effect of telmisartan was partially abolished. Based on these results, increased cardiac miR-154-5p expression is both necessary and sufficient for AngII-induced cardiomyocyte hypertrophy and apoptosis, suggesting that the upregulation of miR-154-5p may be a crucial pathological factor and a potential therapeutic target for cardiac remodeling.

MicroRNA‑21 and myocardial remodeling with the reduction of the nephron mass

Background and objective.Currently, the role of miRNA‑21 in the development of heart and kidney damage and their interaction remains unclear. Therefore, the aim of this work is to assess the impact of changes in the expression of microRNA‑21 in myocardial tissue in the development of cardiac remodeling with chronic reduction in the mass of active nephrons in the experiment.Design and methods.Wistar drain rats were divided into two groups. The first (control) group included nine falsely operated animals. The second (n = 9) group included rats with step-by-step resection of 5/6 renal tissue. After 4 months after surgery, blood pressure (BP) was measured, heart ultrasound (echocardiography, EchoCG) was performed and the level of relative expression of microRNA‑21 in myocardial tissue was determined.Results. The rats with an experimental decrease in the mass of functioning nephrons, showed significantly higher levels of BP, microRNA‑21 expression in the myocardium and the thickness of the interventricular septum (according to EchoCG). They also demonstrated smaller end-systolic dimension of the left ventricle and systolic motion of the mitral valve ring.Conclusions. Our data indicate the potential role of miRNA‑21 in the development of concentric left ventricular remodeling while reducing the number of functioning nephrons. This remodeling is characterized by the prevalence of myocardial hypertrophy over fibrosis. However, the specific mechanisms linking microRNA in the pathogenesis of heart remodeling require further research.