Protective effect and mechanism of estrogen receptor β on myocardial infarction in mice.
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ABSTRACT:
SUBMITTER: Zhang JB
PROVIDER: S-EPMC5526156 | biostudies-other | 2017 Aug
REPOSITORIES: biostudies-other
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Project description:BackgroundLiriodendrin is a therapeutic constituent of sargentgloryvine stem which is a famous Chinese traditional medicine. Previous studies have suggested liriodendrin could inhibit different pathways to treat inflammation in lung and intestinal tract. But whether it can treat myocardial infarction (MI) is unknown. We investigated the protective effect of liriodendrin on acute MI in rats and explored the specific mechanisms to expand the use of this traditional Chinese medicine.MethodsThe rats were randomized into the sham group (sham operation), control group (ligation of the left anterior descending artery), and liriodendrin group. The liriodendrin group was intragastrically administered with a liriodendrin solution (100 mg/kg). The control group and the sham group were intragastrically administered with normal saline. Before all rats were euthanized, echocardiography was used to detect their cardiac function. Hematoxylin and eosin (HE) staining and the terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) method were performed. Further quantitative detection of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) levels in tissues were also detected. Western Blot and real-time polymerase chain reaction (RT-PCR) were used to detect the apoptosis and nuclear factor kappa-B (NF-κB) pathway in tissues. H9C2 cells were used to detect the related mechanisms in vitro.ResultsEchocardiography showed that, compared to control group, the cardiac function of the liriodendrin group was significantly improved. histopathological staining of the control group showed that the myocardial tissue was severely damaged, and inflammatory cells were infiltrated. Compared to the control group, the apoptosis index of the liriodendrin group was significantly lower (P<0.05). Enzyme-linked immunosorbent assay (ELISA) results showed that the levels of IL-1β and TNF-α in the control group were higher than those in the liriodendrin group (P<0.05). Meanwhile, apoptosis and the NF-κB pathway were inhibited after liriodendrin administration (P<0.05). Moreover, the mRNA transcriptional activity in the control group was also higher than that in the liriodendrin group (P<0.05). Because of the effect of liriodendrin, NF-κB pathway and apoptosis were downregulated in H9C2 cells which were exposed to ischemia-hypoxia.ConclusionsLiriodendrin may protect myocardial cells after myocardial infarction in rats by inhibiting the release of inflammatory factors, activation of the NF-κB pathway, and apoptosis.
| S-EPMC8828524 | biostudies-literature
Project description:BackgroundMyocardial infarction (MI) is a major risk factor responsible for morbidity and mortality. Xinji'erkang (XJEK) has been clinically used as an effective medication in the treatment of coronary heart disease and myocarditis. The purpose of this study was to investigate the cardioprotective effect of Xinji'erkang on MI mice.MethodsForty male mice were randomly assigned into four groups as follows (n = 10): sham, model, MI with administration of XJEK and fosinopril for four weeks. At the end of studies, hemodynamic parameters and electrocardiography (ECG) were recorded. Heart and body mass were measured and heart weight/body weight (HW/BW) ratio was calculated as index of hypertrophy. The hypertrophy of heart and aorta was examined using the hematoxylin and eosin (HE) staining, and the collagen deposition was evaluated using Van Gieson (VG) staining. Serum nitric oxide level (NO), superoxide dismutase (SOD) activity and malondialdehyde (MDA) concentration were assayed by colorimetric analysis. The expressions of endothelial NO synthetase (eNOS) expression in serum and cardiac tissues were determined using ELISA assay and immunohistochemistry. Angiotensin II (Ang II) in serum and cardiac tissues was measured using ELISA assay. Besides, tumor necrosis factor-α (TNF-α), interleukin1β (IL-1β) and interleukin10 (IL-10) were observed in cardiac tissues with ELISA assay as well.ResultsThe administration of XJEK significantly improved cardiac dysfunction and abnormal ECG with reduced HW/BW ratio and ameliorated cardiomyocyte hypertrophy and collagen deposition compared to MI, which was partly due to the decreased SOD and increased MDA in serum. Moreover, XJEK treatment also improved endothelial dysfunction (ED) with not only enhanced eNOS activities in serum and cardiac tissues and elevated NO levels in serum, but also decreased Ang II content in serum and cardiac tissues. Finally, protein expressions of pro-inflammation cytokines, TNF-α and IL-1β in the cardiac tissues with XJEK treatment were significantly decreased compared to model. On the contrary, IL-10, an anti-inflammatory cytokine concentrated in cardiac tissues was significantly enhanced compared to model.ConclusionXinji'erkang exerts cardioprotective effect on myocardial infarction in mice, which may be due to the improvement of endothelial dysfunction and the reduction of oxidative stress and inflammation response.
| S-EPMC5485507 | biostudies-literature
Project description:Most seven transmembrane receptors (7TMRs) are G protein-coupled receptors; however, some 7TMRs evoke intracellular signals through β-arrestin as a biased receptor. As several β-arrestin-biased agonists have been reported to be cardioprotective, we examined the role of the chemokine receptor CXCR7 as a β-arrestin-biased receptor in the heart. Among 510 7TMR genes examined, Cxcr7 was the most abundantly expressed in the murine heart. Single-cell RNA-sequencing analysis revealed that Cxcr7 was abundantly expressed in cardiomyocytes and fibroblasts. Cardiomyocyte-specific Cxcr7 null mice showed more prominent cardiac dilatation and dysfunction than control mice 4 weeks after myocardial infarction. In contrast, there was no difference in cardiac phenotypes between fibroblast-specific Cxcr7-knockout mice and control mice even after myocardial infarction. TC14012, a specific agonist of CXCR7, significantly recruited β-arrestin to CXCR7 in CXCR7-expressing cells and activated extracellular signal-regulated kinase (ERK) in neonatal rat cardiomyocytes. Cxcr7 expression was significantly increased and ERK was activated in the border zone of the heart in control, but not Cxcr7 null mice. These results indicate that the abundantly expressed CXCR7 in cardiomyocytes may play a protective role in the heart as a β-arrestin-biased receptor and that CXCR7 may be a novel therapeutic target for myocardial infarction.
| S-EPMC7873251 | biostudies-literature
Project description:Myocardial infarction (MI) is a worldwide disease with high morbidity and mortality and a major cause of chronic heart failure, seriously affecting patients' quality of life. Natural medicine has been used to cure or prevent cardiovascular disease for decades. As a natural flavonoid, Antocyanide has been used to treat many diseases due to its antioxidative, anti-inflammatory, and others. However, the molecular mechanism of Cyanidin (Cyn) in MI is not precise. As demonstrated by the result, after MI, some genes such as Fibronectin 1(Fn1) and Matrix metalloproteinases (MMP2/9) is highly overexpressed, and Cyn protects myocardial cell apoptosis by regulating these genes. These results were warranted by autodocking simulation.
2023-05-01 | GSE203150 | GEO
Project description:Beta-blocker therapy after acute myocardial infarction (MI) improves survival. Beta-blocker doses used in clinical practice are often substantially lower than those used in the randomized trials establishing their efficacy.This study evaluated the association of beta-blocker dose with survival after acute MI, hypothesizing that higher dose beta-blocker therapy will be associated with increased survival.A multicenter registry enrolled 7,057 consecutive patients with acute MI. Discharge beta-blocker dose was indexed to the target beta-blocker doses used in randomized clinical trials, grouped as >0% to 12.5%, >12.5% to 25%, >25% to 50%, and >50% of target dose. Follow-up vital status was assessed, with the primary endpoint of time-to-death right-censored at 2 years. Multivariable and propensity score analyses were used to account for group differences.Of 6,682 patients with follow-up (median 2.1 years), 91.5% were discharged on a beta-blocker (mean dose 38.1% of the target dose). Lower mortality was observed with all beta-blocker doses (p < 0.0002) versus no beta-blocker therapy. After multivariable adjustment, hazard ratios for 2-year mortality compared with the >50% dose were 0.862 (95% confidence interval [CI]: 0.677 to 1.098), 0.799 (95% CI: 0.635 to 1.005), and 0.963 (95% CI: 0.765 to 1.213) for the >0% to 12.5%, >12.5% to 25%, and >25% to 50% of target dose groups, respectively. Multivariable analysis with an extended set of covariates and propensity score analysis also demonstrated that higher doses were not associated with better outcome.These data do not demonstrate increased survival in patients treated with beta-blocker doses approximating those used in previous randomized clinical trials compared with lower doses. These findings provide the rationale to re-engage in research to establish appropriate beta-blocker dosing after MI to derive optimal benefit from this therapy. (The PACE-MI Registry Study-Outcomes of Beta-blocker Therapy After Myocardial Infarction [OBTAIN]: NCT00430612).
| S-EPMC4583654 | biostudies-literature
Project description:PurposeOestrogen receptor β is believed to exert a cardioprotective effect against ischaemic injury. Nonetheless, the mechanism underlying its protective action remains to be fully elucidated. Recently, increased attention has been focused on Notch1 signalling for ameliorating cardiac ischaemic injury. Here, we hypothesised that oestrogen receptor β activation attenuates myocardial infarction (MI)-induced cardiac damage by modulating the Notch1 signalling pathway.MethodsMale C57BL/6 mice were used to establish an MI model through the ligation of the anterior descending branch of the left coronary artery. Two chemical drugs, 2,3-Bis(4-hydroxyphenyl)-propionitrile (DPN) and N-[N-(3,5-difluorophenacetyl)-l-alanyl]-s-phenylglycine t-butyl ester (DAPT), a specific inhibitor of Notch1 signalling) were administered via intraperitoneal injection to change oestrogen receptor β and Notch1 activities. Immunohistochemistry, western blot analysis, enzyme-linked immunosorbent assay (Elisa) assessment and echocardiography were used in this study to analyse cardiac oxidative stress, apoptosis, infraction volume, fibrosis and cardiac function.ResultsDPN-mediated oestrogen receptor β activation effectively protected cardiomyocytes from MI-induced oxidative damage and apoptosis. Furthermore, oestrogen receptor β activation reduced the infarct size and lowered the levels of myocardial enzymes in the serum, thereby leading to greater overall cardiac function improvement. Ischaemic injury-induced myocardial fibrosis was attenuated by oestrogen receptor β activation. Nevertheless, all of these cardioprotective effects of oestrogen receptor β activation were almost abrogated by DAPT administration, i.e. DAPT attenuated the anti-oxidative and anti-apoptotic effects and the decrease in infarct and fibrotic areas and reversed cardiac functional recovery. The levels of phospho-phosphatidylinositol-3-kinase (PI3K) and phospho-protein kinase B (Akt) were increased after DPN administration, and this change was reversed after DAPT was administered.ConclusionsAll of these new findings indicate that oestrogen receptor β activation is effective in ameliorating MI-induced cardiac dysfunction by enhancing Notch1 signalling and that PI3K/Akt signalling is the downstream mediator.
| S-EPMC7223456 | biostudies-literature
Project description:Background This study was aimed at exploring the biological function and molecular mechanism of ferroptosis of LRP6 modulation in cardiomyocytes of myocardial infarction (MI). Method We established the ferroptosis model of MI in vivo and in vitro and constructed the modulation network of circRNA-miRNA-LRP6 by bioinformatics analysis; then, we focused on exploring the regulatory relationship of LRP6 and its upstream genes circRNA1615 and miR-152-3p in the RIP experiments and the double luciferase reporter gene assay. Also, we tested the LRP6-mediated autophagy-related ferroptosis in MI. Results Ferroptosis was found in cardiomyocytes of MI, and ferroptosis inhibitor Ferrostatin-1 (Fer-1) could improve the pathological process of MI. LRP6 was involved in the process of ferroptosis in cardiomyocytes, and LRP6 deletion regulated ferroptosis in cardiomyocytes through autophagy. Screening and identification of the upstream gene circRNA1615 would target LRP6. circRNA1615 inhibited ferroptosis in cardiomyocytes, and circRNA1615 could regulate the expression of LRP6 through sponge adsorption of miR-152-3p, prevent LRP6-mediated autophagy-related ferroptosis in cardiomyocytes, and finally control the pathological process of MI. Conclusions circRNA1615 inhibits ferroptosis via modulation of autophagy by the miRNA152-3p/LRP6 molecular axis in cardiomyocytes of myocardial infarction.
| S-EPMC8548150 | biostudies-literature
Project description:To evaluate the effects and safety of sacubitril/valsartan in patients with acute myocardial infarction (AMI), a total of four databases, including PubMed, Cochrane Library, Embase and Web of Science, and the ClinicalTrials.gov website were searched. Using a combination of medical subject headings and entry terms, the final search was performed in July 2021. A manual search of cross-references from the original articles was also conducted. The meta-analysis was subsequently performed with Revman 5.3 software and a total of four studies comprising 586 patients were included. The results disclosed a significant reduction in major adverse cardiovascular and cerebrovascular events (MACCEs) [odds ratio (OR), 0.47; 95% confidence interval (CI), 0.30-0.73; P=0.0007], readmission (OR, 0.45; 95% CI, 0.29-0.71; P=0.0006), incidence of acute heart failure (AHF) (OR, 0.45; 95% CI, 0.28-0.71; P=0.0007) and N-terminal pro B-type natriuretic peptide [standardized mean difference (SMD), -0.88; 95% CI, -1.55-(-0.21); P=0.01] in the sacubitril/valsartan group compared with that in the control group, and a random effects model was used to pool these data. No significant differences were identified in the incidence of hypotension (OR, 2.91; 95% CI, 0.55-15.51; P=0.21), adverse events (OR, 2.19; 95% CI, 0.42-11.37; P=0.35), left ventricular ejection fraction (mean difference, 1.96; 95% CI, -0.84-4.76; P=0.17) or soluble suppression of tumorigenesis-2 (SMD, -0.45; 95% CI, -1.62-0.71; P=0.45) according to the random effects model. In conclusion, the present meta-analysis revealed that sacubitril/valsartan was able to effectively reduce the incidence of MACCEs, readmission and AHF in patients with AMI after revascularization without any obvious adverse events.
| S-EPMC9115635 | biostudies-literature
Project description:Transforming growth factor beta (TGFβ) plays a crucial role in tissue fibrosis. A number of studies have shown that TGFβ3 significantly attenuated tissue fibrosis. However, the mechanism involved in this effect is poorly understood. In this study we found that the expression level of TGFβ3 was higher in human myocardial infarction (MI) tissues than in normal tissues, and interestingly, it increased with the development of fibrosis post-myocardial infarction (post-MI). In vitro, human cardiac fibroblasts (CFs) were incubated with angiotensin II (Ang II) to mimic the ischaemic myocardium microenvironment and used to investigate the anti-fibrotic mechanism of TGFβ3. Then, fibrosis-related proteins were detected by Western blot. It was revealed that TGFβ3 up-regulation attenuated the proliferation, migration of human CFs and the expression of collagens, which are the main contributors to fibrosis, promoted the phenotype shift and the cross-linking of collagens. Importantly, the expression of collagens was higher in the si-smad7 groups than in the control groups, while silencing smad7 increased the phosphorylation level of the TGFβ/smad signalling pathway. Collectively, these results indicated that TGFβ3 inhibited fibrosis via the TGFβ/smad signalling pathway, possibly attributable to the regulation of smad7, and that TGFβ3 might serve as a potential therapeutic target for myocardial fibrosis post-MI.
| S-EPMC6533491 | biostudies-literature
Project description:Glucagon is a hormone with metabolic actions that maintains normoglycemia during the fasting state. Strategies enabling either inhibition or activation of glucagon receptor (Gcgr) signaling are being explored for the treatment of diabetes or obesity. However, the cardiovascular consequences of manipulating glucagon action are poorly understood.We assessed infarct size and the following outcomes following left anterior descending (LAD) coronary artery ligation; cardiac gene and protein expression, acylcarnitine profiles, and cardiomyocyte survival in normoglycemic non-obese wildtype mice, and in newly generated mice with selective inactivation of the cardiomyocyte Gcgr. Complementary experiments analyzed Gcgr signaling and cell survival in cardiomyocyte cultures and cell lines, in the presence or absence of exogenous glucagon.Exogenous glucagon administration directly impaired recovery of ventricular pressure in ischemic mouse hearts ex vivo, and increased mortality from myocardial infarction after LAD coronary artery ligation in mice in a p38 MAPK-dependent manner. In contrast, cardiomyocyte-specific reduction of glucagon action in adult Gcgr (CM-/-) mice significantly improved survival, and reduced hypertrophy and infarct size following myocardial infarction. Metabolic profiling of hearts from Gcgr (CM-/-) mice revealed a marked reduction in long chain acylcarnitines in both aerobic and ischemic hearts, and following high fat feeding, consistent with an essential role for Gcgr signaling in the control of cardiac fatty acid utilization.Activation or reduction of cardiac Gcgr signaling in the ischemic heart produces substantial cardiac phenotypes, findings with implications for therapeutic strategies designed to augment or inhibit Gcgr signaling for the treatment of metabolic disorders.
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