Abstract 13408: Tumor Endothelial Marker 1 is Upregulated in Cardiomyocytes and Participates in Cardiac Remodeling After Cardiac Injury

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Yi-Heng Li ◽  
Po-Sheng Chen ◽  
Wen-Han Feng ◽  
Hsing-Chun Chung
Keyword(s):  
Western Blot ◽  
Cardiac Remodeling ◽  
Transmembrane Protein ◽  
Cardiac Injury ◽  
Fold Increase ◽  
Mechanical Stretch ◽  
H9c2 Cells ◽  
Study Results ◽  
Endothelial Marker

Background: Tumor endothelial marker 1 (TEM1), also known as endosialin or CD248, is a transmembrane protein that expresses in mesenchymal lineage-derived cells only during embryogenesis and becomes undetectable in normal tissues after birth. Re-expression of TEM1 is found on activated cells of mesenchymal lineage during pathological conditions, such as stroma cells in cancer, fibroblasts in organ fibrosis and wound healing, indicating its potential role in tissue remodeling and repair. The expression levels and physiological functions of TEM1 in heart are unknown. Methods and Results: All data were presented as mean ± standard error. In 2 explanted hearts from patients with heart failure (HF) received heart transplantation, immunofluorescence staining showed TEM1 was highly expressed in cardiomyocytes (CMs) and also in cardiac fibroblasts. In mouse HF models induced by intraperitoneal doxorubicin injection (5 mg/kg/wk for 4 wks) or coronary ligation, immunohistochemistry study showed TEM1 expression in hearts. Western blot showed 1.23±0.02 and 1.56±0.04-fold increase of cardiac TEM1 expression compared to controls, respectively. In vitro studies showed TEM1 expression increased in cultured CMs (H9C2 cells) treated with: (1) mechanical stretch (10% elongation at 60 cycles/min) (0 vs 0.5 vs 1 vs 3 hr, Western blot ratio: 1 vs 1.86±0.20 vs 1.87±0.20 vs 1.21±0.21, p<0.05), (2) doxorubicin (100 nM) (0 vs 0.5 vs 2 vs 4 hr: 1 vs 0.70±0.22 vs 1.75±0.26 vs 1.84±0.24, p<0.05) and (3) hypoxia (1% O2) (0 vs 0.5 vs 2 vs 4 hr: 1 vs 1.70±0.06 vs 1.49±0.22 vs 2.07±0.35, p<0.05). Recombinant TEM1 (rTEM1) promoted proliferation of H9C2 cells (saline vs rTEM1 50 vs 100 vs 250 nM, BrdU absorbance: 1.23±0.03 vs 1.36±0.03 vs 1.37±0.05 vs 1.38±0.02, p<0.05), reduced doxorubicin (1uM)-induced apoptosis (apoptosis ratio: 1 vs 0.89±0.02 vs 0.91±0.01 vs 0.88±0.05, p<0.05), increased cell hypertrophy (cell area ratio: 1 vs 1.11±0.21 vs 1.51±0.18 vs 1.63±0.13, p<0.05) and increased collagen production from CMs (collagen 3 Western blot ratio: 1 vs 1.49±0.15 vs 1.53±0.19 vs 1.29±0.24, p<0.05). Conclusions: Our study results indicate that TEM1 is upregulated in CMs after cardiac injury and influences the cell behaviors of CMs that related to cardiac remodeling.

Abstract 1770: Proteasome Switching is Associated with Adverse Cardiac Remodeling in a Transgenic Mouse Model of Sustained Inflammatory Signaling

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Wei Wang ◽  
Gabor Szalai ◽  
Natarajan Sivasubramanian ◽  
Douglas L Mann
Keyword(s):  
Proteolytic Activity ◽  
Cardiac Remodeling ◽  
Fold Increase ◽  
Left Ventricular ◽  
26S Proteasome ◽  
Myocardial Inflammation ◽  
Fluorescent Substrate ◽  
Lv Remodeling ◽  
Apoptotic Proteins

The 26S proteasome possess proteolytic activity and deubiquitinating (DUB) activity of ubiquitin tagged proteins. Whereas the proteolytic activity of the 26S proteasome facilitates protein degradation, proteasome DUB activity spares proteins from degradation by shortening the length of the ubiquitin chains, thereby preventing proteins from being degraded by the 26S proteasome. In yeast, increased DUB activity is beneficial by preventing depletion of ubiquitin pools critical for cell signaling. However, the role of DUB activity in mammalian systems is not known. We have shown that mice with cardiac restricted overexpression of tumor necrosis factor (sTNF mice) develop a heart failure phenotype characterized by progressive left ventricular (LV) remodeling and accumulation of pro-apoptotic proteins, including Smac/Diablo. To determine whether the adverse LV remodeling in sTNF mice was related to alterations in DUB activity we measured the cleavage of ubiquitin-AMC, an in vitro fluorescent substrate for DUBs, in purified preparations of the 26S proteasome obtained from hearts of 4 week old sTNF and littermate (LM) control mice. Compared to LM controls we observed a significant (p < 0.001) 60.8% decrease in activity of the 26S proteasome and a significant (p < 0.01) 24.2% increase in DUB activity in sTNF mouse hearts. There was also a significant (p < 0.01) 11-fold increase myocardial protein levels of USP14, a critical DUB associated with the 26S proteasome in sTNF mouse hearts. The decrease in 26S proteasome activity and increased DUB activity in sTNF mouse hearts was accompanied by an increase in myocardial levels of ubiquitinated SMAC/Diablo. Taken together these results show for the first time that sustained myocardial inflammation leads to switch in the function of the proteasome from a proteolytic function to a protein sparing function. Although this “proteasome switching” may provide a short-term adaptive benefit by preventing depletion of critical ubiquitin pools, it may lead to long-term maladaptive consequences by allowing the progressive accumulation of potentially harmful pro-apoptotic proteins in the cytosol, which may in turn promote programmed cell death and adverse cardiac remodeling.

Abstract 15142: Endogenous Cardiac Stem Cells’ Activation in Response to Injury Potentiates Their Regenerative Ability

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Andrew J Smith ◽  
Iolanda Aquila ◽  
Beverley J Henning ◽  
Mariangela Scalise ◽  
Bernardo Nadal-Ginard ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cardiac Injury ◽  
Fold Increase ◽  
Cardiac Stem Cells ◽  
Post Injury ◽  
Activated State ◽  
Potential Benefits ◽  
Therapeutic Avenue

The identification of resident, endogenous cardiac stem cells (eCSCs) has re-shaped our understanding of cardiac cellular physiology, while offering a significant potential therapeutic avenue. The biology of these cells must be better understood to harness their potential benefits. We used an acute dose (s.c.; 5mgkg-1) of isoproterenol (ISO) to induce diffuse cardiac injury, with associated eCSC activation, in rats. As peak eCSC activation was at 24 hours post ISO-injury, c-kitpos eCSCs were isolated, characterised and their potential for growth and regenerative potential was assessed in vitro and in vivo, respectively. Activated eCSCs showed increased cell cycling activity (51+1% in S- or G2/M phases vs. 9+2% of quiescent), Ki67 expression (56+7% vs. 10+1%) and TERT expression (14-fold increase vs. quiescent). When directly harvested in culture, activated eCSCs showed augmented proliferation, clonogenicity and cardiosphere formation compared to quiescent eCSCs. Activated eCSCs showed increases in expression of numerous growth factors, particularly HGF, IGF-1, TGF-β, periostin, PDGF-AA and VEGF-A. Furthermore, significant alterations were found in the miRnome, notably increased miR-146b and -221, and decreased miR-192 and -351. ISO+5FU was administrated to mice to induce a model of chronic dilated cardiomyopathy, which is characterized by the ablation of eCSCs and the absence of cardiomyocyte replenishment. In these mice with chronic heart failure, freshly isolated quiescent eCSCs or activated eCSCs (2d post-ISO) were injected through the tail vein. 28 days after injection, activated but not quiescent eCSCs re-populated the resident CSC pool, promoted robust new cardiomyocyte formation and improved cardiac function when compared to saline-treated mice. Dual-labelling with BrdU and EdU at selected stages after ISO injury determined that activated eCSCs returned to a quiescent level by 10 weeks post-injury. In conclusion, CSCs rapidly switch from a quiescent to an activated state to match the myocardial needs for myocyte replacement after injury and then spontaneously go back to quiescence. Harnessing the molecules regulating this process may open up future novel approaches for effective myocardial regeneration.

scholarly journals Calycosin Alleviates Doxorubicin-Induced Cardiotoxicity and Pyroptosis by Inhibiting NLRP3 Inflammasome Activation

2022 ◽  
Vol 2022 ◽  
pp. 1-15
Author(s):  
Lei Zhang ◽  
Cundong Fan ◽  
Hua-Chen Jiao ◽  
Qian Zhang ◽  
Yue-Hua Jiang ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Cardiac Injury ◽  
H9c2 Cell ◽  
Inflammasome Activation ◽  
Dependent Manner ◽  
H9c2 Cells ◽  
Stress Injury ◽  
Nlrp3 Inflammasome Activation

Calycosin (CAL) is the main active component present in Astragalus and reportedly possesses diverse pharmacological properties. However, the cardioprotective effect and underlying mechanism of CAL against doxorubicin- (DOX-) induced cardiotoxicity need to be comprehensively examined. Herein, we aimed to investigate whether the cardioprotective effects of CAL are related to its antipyroptotic effect. A cardiatoxicity model was established by stimulating H9c2 cells and C57BL/6J mice using DOX. In vitro, CAL increased H9c2 cell viability and decreased DOX-induced pyroptosis via NLRP3, caspase-1, and gasdermin D signaling pathways in a dose-dependent manner. In vivo, CAL-DOX cotreatment effectively suppressed DOX-induced cytotoxicity as well as inflammatory and cardiomyocyte pyroptosis via the same molecular mechanism. Next, we used nigericin (Nig) and NLRP3 forced overexpression to determine whether CAL imparts antipyroptotic effects by inhibiting the NLRP3 inflammasome in vitro. Furthermore, CAL suppressed DOX-induced mitochondrial oxidative stress injury in H9c2 cells by decreasing the generation of reactive oxygen species and increasing mitochondrial membrane potential and adenosine triphosphate. Likewise, CAL attenuated the DOX-induced increase in malondialdehyde content and decreased superoxide dismutase and glutathione peroxidase activities in H9c2 cells. In vivo, CAL afforded a protective effect against DOX-induced cardiac injury by improving myocardial function, inhibiting brain natriuretic peptide, and improving the changes of the histological morphology of DOX-treated mice. Collectively, our findings confirmed that CAL alleviates DOX-induced cardiotoxicity and pyroptosis by inhibiting NLRP3 inflammasome activation in vivo and in vitro.

scholarly journals Inhibition of ADAM10 ameliorates doxorubicin-induced cardiac remodeling by suppressing N-cadherin cleavage

2021 ◽  
Vol 16 (1) ◽  
pp. 856-866
Author(s):  
Xiaoou Li ◽  
Feng Pan ◽  
Bing He ◽  
Chengzhi Fang
Keyword(s):  
Cardiac Remodeling ◽  
Myocardial Dysfunction ◽  
H9c2 Cells ◽  
Hairpin Rna ◽  
Adhesion Ability ◽  
Adhesion Model ◽  
Short Hairpin ◽  
Reverse Cardiac Remodeling

Abstract The present research was designed to examine the effects of disintegrin metalloproteinases 10 (ADAM10) on the doxorubicin (DOX)-induced dilated cardiomyopathy (DCM) and the mechanisms involved, with a focus on ADAM10-dependent cleavage of N-cadherin. The present study constructed recombinant lentiviral vectors expressing short hairpin RNA (shRNA) targeting the ADAM10 gene. H9C2 cells were treated with the recombinant lentivirus or GI254023 (an ADAM10 inhibitor). The expression level of N-cadherin and its C-terminal fragment1 (CTF1) was tested by western blotting and flow cytometry. The adhesion ability was analyzed using a plate adhesion model. Cardiac function and morphology were assessed in control and lentivirus-transfected rats with or without DOX treatment. The inhibition of ADAM10 activity significantly increased the expression of full-length N-cadherin on the cellular surface and reduced CTF1 generation in vivo and in vitro. The adhesion ability was also increased in ADAM10-knockdown H9C2 cells. Furthermore, DOX-induced myocardial dysfunction was ameliorated in rats transfected with ADAM10-shRNA lentivirus. These findings demonstrated that ADAM10 specifically cleaves N-cadherin in cardiomyocytes. ADAM10-induced N-cadherin cleavage results in changes in the adhesive behavior of cells. Therefore, ADAM10 may serve as a therapeutic target to reverse cardiac remodeling in DCM.

Rosuvastatin corrects oxidative stress and inflammation induced by LPS to attenuate cardiac injury by inhibiting the NLRP3/TLR4 pathway

2021 ◽  
Author(s):  
Guocheng Ren ◽  
Qiujie Zhou ◽  
Meili Lu ◽  
Hongxin Wang
Keyword(s):  
Oxidative Stress ◽  
Inflammatory Response ◽  
Cardiac Injury ◽  
H9c2 Cells ◽  
Sod Activity ◽  
Lps Challenge ◽  
Pathway Activation ◽  
Underlying Mechanisms

The aim of the current study was to evaluate whether rosuvastatin was effective in attenuating cardiac injury in lipopolysaccharide(LPS)-challenged mice and H9C2 cells and identify the underlying mechanisms, focusing on the NLRP3/TLR4 pathway. Cardiac injury, cardiac function, apoptosis, oxidative stress, inflammatory response and the NLRP3/TLR4 pathway were evaluated in both in vivo and in vitro studies. LPS-induced cardiomyocytes injury was markedly attenuated by rosuvastatin treatment. Apoptosis was clearly ameliorated in myocardial tissue and H9C2 cells cotreated with rosuvastatin. In addition, excessive oxidative stress was present, as indicated by increases in MDA content, NADPH activity and ROS production and decreased SOD activity after LPS challenge. Rosuvastatin improved all the indicators of oxidative stress, with a similar effect to NAC(ROS scavenger). Notably, LPS-exposed H9C2 cells and mice showed significant NLRP3 and TLR4/NF-κB pathway activation. Administration of rosuvastatin reduced the increases in expression of NLRP3, ASC, pro-caspase-1, TLR4, and p65 and decreased the contents of TNF-α, IL-1β, IL-18 and IL-6, with a similar effect as MCC950 (NLRP3 inhibitor). In conclusion, inhibition of the inflammatory response and oxidative stress contributes to cardioprotection of rosuvastatin on cardiac injury induced by LPS, and the effect of rosuvastatin was achieved by inactivation of the NF-κB/NLRP3 pathway

SMYD1 alleviates septic myocardial injury by inhibiting endoplasmic reticulum stress

2021 ◽  
Author(s):  
Meixue Chen ◽  
Jing Li ◽  
Jinfeng Wang ◽  
Yuan Le ◽  
Chunfeng Liu
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Heart Development ◽  
Cell Injury ◽  
Cardiac Injury ◽  
Major Complication ◽  
Inflammatory Factors ◽  
H9c2 Cells ◽  
H9c2 Cardiomyocytes

Abstract Sepsis-induced cardiomyopathy (SIC) is a major complication of sepsis. SET and MYND domain containing 1 (SMYD1) has central importance in heart development, and its role in SIC has not been identified. Herein, we found that the expression of SMYD1 was downregulated in myocardial tissues of SIC patients (from GEO database: GSE79962) and lipopolysaccharide (LPS)-induced SIC rats, and LPS-induced H9c2 cardiomyocytes. We used LPS-stimulated H9c2 cells that mimic sepsis in vitro to explore the function of SMYD1 in SIC. MTT assay, LDH and CK-MB release assay, flow cytometry, and ELISA assay showed that SMYD1 overexpression enhanced cell viability, alleviated cell injury, impeded apoptosis, and reduced the level of pro-inflammatory factors and NF-κB activation under the condition of LPS stimulation. Moreover, SMYD1 exerted protective effect on H9c2 cells stimulated with LPS through relieving endoplasmic reticulum (ER) stress. In conclusion, overexpression of SMYD1 alleviates cardiac injury through relieving ER stress during sepsis.

scholarly journals Angiotensin II receptor blocker LCZ696 attenuates cardiac remodeling through the inhibition of the ERK signaling pathway in mice with pregnancy-associated cardiomyopathy

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Yi Wang ◽  
Zhiheng Guo ◽  
Yongmei Gao ◽  
Ping Liang ◽  
Yanhong Shan ◽  
...  
Keyword(s):  
Survival Rate ◽  
Cardiac Hypertrophy ◽  
Signaling Pathway ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Cardiac Injury ◽  
Erk Signaling ◽  
Ang Ii ◽  
Total Survival

Abstract Pregnancy-associated cardiomyopathy (PAH) represents a pregnancy-associated myocardial disease that is characterized by the progression of heart failure due to marked left ventricular systolic dysfunction. Compelling evidence has highlighted the potential of angiotensin (Ang) receptor inhibitors as therapeutic targets in PAH treatment. The present study aims to elucidate the molecular mechanisms underlying Ang II receptor inhibitor LCZ696 treatment in PAH. Initially, a PAH mouse model was induced, followed by intraperitoneal injection of LCZ696. Subsequently, cardiomyocytes and fibroblasts were isolated, cultured, and treated with Ang II and LCZ696, followed by detection of the total survival rate, cardiac injury, cardiac fibrosis and apoptosis. Moreover, in order to quantify the cardiac hypertrophy and fibrosis degree of cardiac fibroblasts, the expression levels of markers of cardiac hypertrophy (ANP, βMHC and TIMP2) and markers of fibrosis (collagen I, collagen III and TGF-β) were evaluated. Furthermore, the potential effect of LCZ696 on the extracellular signal-regulated kinase (ERK) signaling pathway was examined. The acquired findings revealed that LCZ696 increased the total survival rate of PAH mice, but decreased cardiac injury, cardiac fibrosis, and apoptosis in vitro. LCZ696 attenuated cardiac injury induced by Ang II through the inhibition the expression of markers of cardiac hypertrophy, fibrosis and apoptosis by inhibiting ERK phosphorylation in vivo and in vitro. Altogether, LCZ676 could potentially alleviate cardiac remodeling in mice with PAH via blockade of the ERK signaling pathway activation. Our findings suggest that LCZ696 could be a potential target for PAH therapy.

scholarly journals Pomalidomide and Dexamethasone Regulate Human Erythroid Progenitor Signaling through Two Distinct Pathways

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2423-2423
Author(s):  
Brian M. Dulmovits ◽  
Nan Wang ◽  
Corinne LaVasseur ◽  
Julien Papoin ◽  
Hongxia Yan ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Western Blot ◽  
Cord Blood ◽  
Fold Increase ◽  
Vehicle Control ◽  
The Self ◽  
Erythroid Progenitors ◽  
Erythroid Progenitor ◽  
Self Renewal

Abstract With the exception of cytokines, corticosteroids such as dexamethasone (Dex) and the immunomodulatory drugs (IMiDs) such as pomalidomide (Pom) are the primary pharmacologic agents that directly improve red cell production in patients with disordered erythropoiesis. Corticosteroids are the standard of care for patients with Diamond Blackfan anemia (DBA) while the IMiDs are used for patients with myelodysplastic syndrome (MDS) to improve the profound anemia seen in these patients. While it is generally accepted that loss of erythroid progenitors such as burst forming unit-erythroid (BFU-E) and colony forming unit-erythroid (CFU-E) underlie congenital and acquired bone marrow failure syndromes such as DBA and MDS, our limited understanding of the regulatory programs governing erythroid progenitor self-renewal and differentiation hinder development of more specific therapies aimed at increasing erythroid progenitor numbers in these diseases. To investigate the dynamics of erythroid progenitors in normal and diseased states, we used an in vitro culture system consisting of 3 phases to study human erythropoiesis in the presence of Pom or Dex. Our earlier work provided evidence that Pom transcriptionally reprograms adult erythroid progenitors, and delays the BFU-E to CFU-E transition; this delay is through a yet to be characterized mechanism. To elucidate the effects of Pom on erythroid progenitors we differentiated adult CD34+ hematopoietic stem and progenitor cells (HSPCs) and performed gene expression microarray analyses on erythroid cells at day 4. We found that Pom induced significant expression changes in 20 genes including TEA domain transcription factor 2 (TEAD2), a transcription factor involved in stem cell self-renewal and hippo signaling. To date, a function for TEAD2 in human erythropoiesis has not been identified. qRT-PCR and western blot studies validated that Pom induces a greater than 100-fold increase in TEAD2 expression compared to vehicle control. Previous studies have shown that members of the TEAD family cooperate with cytokines such as transforming growth factor-β (TGF-β) and Bone Morphogenic Protein 4 (BMP4), two known modulators of erythropoiesis. We observed that Pom did not affect the levels of phospho-SMAD2 by western blot analysis, a downstream effector of TGF-β. In marked contrast, Pom-treated cells exhibited higher levels of p-SMAD1/5/9 suggesting that Pom may enhance or activate the BMP4 pathway. These data suggest that Pom leads to the self-renewal of BFU-E through the activation of TEAD2. We are currently investigating the downstream signaling pathways involved. The role of Dex in human erythropoiesis is more controversial. Previous studies, particularly in murine models have suggested that the effects of Dex occur at the BFU-E stage. However, in our studies, we found that Dex acts at the level of CFU-E in models of human erythropoiesis. We found that Dex promotes both the self-renewal as well as the differentiation of CFU-E. We found that treatment with dexamethasone resulted in a 4-fold increase in the percentage of CFU-E in culture when compared to vehicle control. Interestingly, these effects vary with the type of HSPC used (peripheral blood vs. cord blood). Indeed, while Dex induced extensive proliferation of adult CFU-Es, it had no effects on CFU-E from cord blood. These results suggest a specificity for corticosteroids during development and suggest that these drugs may prove more useful in certain types of anemia. Finally, clinical data from three different DBA patients demonstrated a response to steroids within a week of treatment, as measured by an increase in reticulocytes suggesting that the population responding to treatment is indeed the CFU-E, reinforcing our in vitro findings. We are now investigating the molecular mechanisms involving the effects of dexamethasone on erythroid progenitors. Together, these results suggest that Pom and Dex may influence erythroid progenitor self-renewal and differentiation through independent mechanisms and that combination therapy may be beneficial for a variety of diseases characterized by disordered erythropoiesis. Disclosures No relevant conflicts of interest to declare.

Abstract 211: Long Noncoding RNA Myocardial Infarction Associated Transcript, MIAT Exacerbates Maladaptive Cardiac Remodeling by Functioning as a Competing Endogenous RNA of MicroRNA-150 During Myocardial Infarction

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Tatsuya Aonuma ◽  
Bruno Moukette ◽  
Il-man Kim
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Remodeling ◽  
Noncoding Rna ◽  
Target Genes ◽  
Cardiac Injury ◽  
Noncoding Rnas ◽  
Nucleotide Polymorphisms ◽  
Competing Endogenous Rna ◽  
Increased Risk

Cardiac injury is accompanied by dynamic changes in the expression of noncoding RNAs such as microRNAs (miRs) and long noncoding RNAs (lncRNAs) that regulate target genes. We previously reported that β 1 -adrenergic receptor/β-arrestin1-responsive miR-150 plays a vital cardioprotective role in myocardial infarction (MI) via decreasing cardiac cell apoptosis (Fig. A). MiR-150 is regulated by MI-Associated Transcript (MIAT), a lncRNA that directly interacts with miR-150 and functions as its competing endogenous RNA in vitro . Gain-of-function single nucleotide polymorphisms in MIAT are associated with increased risk of MI in humans, and MIAT is upregulated in post-MI hearts, concurrent with downregulation of miR-150. Despite the increasing data from both human and rodent studies, the conserved functional MIAT/miR-150 axis in cardiac pathology has never been investigated in genetically modified mice. Here, we hypothesize that MIAT competitively sequesters miR-150 and blocks the inhibitory effect of miR-150 on proapoptotic genes, thereby increasing maladaptive post-MI remodeling. Using novel mouse models, we demonstrate that global genetic deletion of MIAT in mice protects hearts against MI, while genetic overexpression of MIAT worsens maladaptive cardiac remodeling. Moreover, MIAT downregulates miR-150 in the heart, while miR-150 does not repress MIAT. Importantly, we show that miR-150 overexpression prevents the detrimental post-MI effects caused by overexpression of MIAT (Fig. B). In conclusion, these findings reveal a pivotal functional interaction between MIAT and miR-150 as a novel epigenetic regulatory mechanism pertinent to ischemic cardiac injury.

scholarly journals Rosuvastatin protects against coronary microembolization-induced cardiac injury via inhibiting NLRP3 inflammasome activation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ao Chen ◽  
Zhangwei Chen ◽  
You Zhou ◽  
Yuan Wu ◽  
Yan Xia ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Molecular Mechanisms ◽  
Cardiac Injury ◽  
Serum Lactate Dehydrogenase ◽  
Inflammasome Activation ◽  
H9c2 Cells ◽  
Iodide Uptake ◽  
Coronary Microembolization ◽  
Mitochondrial Ros

AbstractCoronary microembolization (CME), a common reason for periprocedural myocardial infarction (PMI), bears very important prognostic implications. However, the molecular mechanisms related to CME remain largely elusive. Statins have been shown to prevent PMI, but the underlying mechanism has not been identified. Here, we examine whether the NLRP3 inflammasome contributes to CME-induced cardiac injury and investigate the effects of statin therapy on CME. In vivo study, mice with CME were treated with 40 mg/kg/d rosuvastatin (RVS) orally or a selective NLRP3 inflammasome inhibitor MCC950 intraperitoneally (20 mg/kg/d). Mice treated with MCC950 and RVS showed improved cardiac contractile function and morphological changes, diminished fibrosis and microinfarct size, and reduced serum lactate dehydrogenase (LDH) level. Mechanistically, RVS decreased the expression of NLRP3, caspase-1, interleukin-1β, and Gasdermin D N-terminal domains. Proteomics analysis revealed that RVS restored the energy metabolism and oxidative phosphorylation in CME. Furthermore, reduced reactive oxygen species (ROS) level and alleviated mitochondrial damage were observed in RVS-treated mice. In vitro study, RVS inhibited the activation of NLRP3 inflammasome induced by tumor necrosis factor α plus hypoxia in H9c2 cells. Meanwhile, the pyroptosis was also suppressed by RVS, indicated by the increased cell viability, decreased LDH and propidium iodide uptake in H9c2 cells. RVS also reduced the level of mitochondrial ROS generation in vitro. Our results indicate the NLRP3 inflammasome-dependent cardiac pyroptosis plays an important role in CME-induced cardiac injury and its inhibitor exerts cardioprotective effect following CME. We also uncover the anti-pyroptosis role of RVS in CME, which is associated with regulating mitochondrial ROS.

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