Exercise restores dysregulated gene expression in a mouse model of arrhythmogenic cardiomyopathy

Abstract Aims Arrhythmogenic cardiomyopathy (ACM) is a myocardial disease caused mainly by mutations in genes encoding desmosome proteins ACM patients present with ventricular arrhythmias, cardiac dysfunction, sudden cardiac death, and a subset with fibro-fatty infiltration of the right ventricle predominantly. Endurance exercise is thought to exacerbate cardiac dysfunction and arrhythmias in ACM. The objective was to determine the effects of treadmill exercise on cardiac phenotype, including myocyte gene expression in myocyte-specific desmoplakin (Dsp) haplo-insufficient (Myh6-Cre:DspW/F) mice. Methods and results Three months old sex-matched wild-type (WT) and Myh6-Cre:DspW/F mice with normal cardiac function, as assessed by echocardiography, were randomized to regular activity or 60 min of daily treadmill exercise (5.5 kJ work per run). Cardiac myocyte gene expression, cardiac function, arrhythmias, and myocardial histology, including apoptosis, were analysed prior to and after 3 months of routine activity or treadmill exercise. Fifty-seven and 781 genes were differentially expressed in 3- and 6-month-old Myh6-Cre:DspW/F cardiac myocytes, compared to the corresponding WT myocytes, respectively. Genes encoding secreted proteins (secretome), including inhibitors of the canonical WNT pathway, were among the most up-regulated genes. The differentially expressed genes (DEGs) predicted activation of epithelial–mesenchymal transition (EMT) and inflammation, and suppression of oxidative phosphorylation pathways in the Myh6-Cre:DspW/F myocytes. Treadmill exercise restored transcript levels of two-third (492/781) of the DEGs and the corresponding dysregulated transcriptional and biological pathways, including EMT, inflammation, and secreted inhibitors of the canonical WNT. The changes were associated with reduced myocardial apoptosis and eccentric cardiac hypertrophy without changes in cardiac function. Conclusion Treadmill exercise restored transcript levels of the majority of dysregulated genes in cardiac myocytes, reduced myocardial apoptosis, and induced eccentric cardiac hypertrophy without affecting cardiac dysfunction in a mouse model of ACM. The findings suggest that treadmill exercise has potential beneficial effects in a subset of cardiac phenotypes in ACM.

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Effects of treadmill exercise on recovery of cardiac function in a mouse model of myocardial infarction

Exercise Science ◽

10.15857/ksep.2013.22.2.151 ◽

2013 ◽

Vol 22 (2) ◽

pp. 151-161

Author(s):

김동환 ◽

김미자 ◽

소용석 ◽

Young-Jun Kim ◽

Yoon, Mi-Yeon ◽

...

Keyword(s):

Myocardial Infarction ◽

Mouse Model ◽

Cardiac Function ◽

Treadmill Exercise

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Ataxia-telangiectasia mutated protein protects cardiac cells from stress by rewiring glucose metabolism

European Heart Journal ◽

10.1093/ehjci/ehaa946.3616 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

R Paolillo

Keyword(s):

Gene Expression ◽

Cardiac Function ◽

Cardiac Dysfunction ◽

Ataxia Telangiectasia ◽

Pressure Overload ◽

Cardiac Metabolism ◽

Mitochondrial Morphology ◽

Funding Source ◽

Ataxia Telangiectasia Mutated ◽

Pyruvate Oxidation

Abstract Introduction Pressure overload-induced cardiac hypertrophy is associated with increased reactive oxygen species (ROS), inducing DNA damage and activating the protein kinase Ataxia-Telangiectasia Mutated (ATM). Recently, ATM has been also involved in the regulation of several metabolic processes, but whether and how it affects cardiac metabolism is still poorly understood. Purpose We hypothesized that ATM might play crucial roles in the maintenance of cardiomyocyte metabolic homeostasis and in the development of cardiac dysfunction in response to pressure overload. Methods Atm+/+ and Atm homozygous mutated mice (Atm−/−) underwent transverse aortic constriction (TAC) or sham operation (sham). After one week (1w), sham and TAC mice were anesthetized, cardiac function and morphometry were analyzed, and gene expression reprogramming, cardiac histology, mitochondrial morphology were performed. Metabolic profiling was carried out through untargeted metabolomics (LC-MS/MS and GC/MS), mRNA and/or protein levels analysis to investigate glycolyis, pyruvate oxidation, Krebs cycle, aminoacid synthesis, gluconeogenesis and lipid oxidation. Results Atm genetic inactivation induced cardiomyocytes hypertrophy and fetal gene reprogramming in sham mice, with normal cardiac function and in the absence of fibrosis or mitochondrial dysfunction (Figure 1A). After TAC 1w, cardiac function was significantly decreased in Atm−/− mice, compared to Atm+/+ (Figure 1B). In both sham and TAC 1w Atm−/− mice, significant metabolic abnormalities were identified, including switching of glycolysis, reduction of pyruvate oxidation (Figure 1B), activation of aminoacid synthesis and accumulation of long and short-chain fatty acid conjugated with carnitine. Pyruvate accumulation was associated to a significant reduction of pyruvate carrier (MPC1-MPC2) and pyruvate dehydrogenase (PDH) levels in sham and TAC 1w Atm−/− mice. Conclusions ATM regulates gene expression, cardiomyocyte hypertrophy and cardiac responses to pressure overload, modulating cardiac metabolism and the profile of intracellular substrate utilization in the heart. Thus, ATM might represent a novel important player in the development of cardiac dysfunction and a novel therapeutic target. Figure 1 Funding Acknowledgement Type of funding source: Other. Main funding source(s): CP was supported by Ministero dell'Istruzione, Università e Ricerca Scientifica grant (2015583WMX) and Programma STAR grant by Federico II University and Compagnia di San Paolo. RP was supported by a research grant provided by the Cardiopath PhD program.

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Abstract 50: Therapeutic Silencing of miRNA-652 Restores Cardiac Function and Attenuates Pathological Remodeling in a Mouse Model of Pressure Overload

Circulation Research ◽

10.1161/res.115.suppl_1.50 ◽

2014 ◽

Vol 115 (suppl_1) ◽

Author(s):

Bianca C Bernardo ◽

Sally S Nguyen ◽

Catherine E Winbanks ◽

Xiao-Ming Gao ◽

Esther J Boey ◽

...

Keyword(s):

Heart Failure ◽

Mouse Model ◽

Cardiac Function ◽

Cardiac Dysfunction ◽

Heart Function ◽

Pressure Overload ◽

Post Treatment ◽

Locked Nucleic Acid ◽

Luciferase Assay ◽

Sham Operation

Introduction: Targeting microRNAs differentially regulated in settings of stress and protection could represent a new approach for the treatment of heart failure. miR-652 expression increased in hearts of a cardiac stress mouse model and was downregulated in a model of cardiac protection. Aim: To assess the therapeutic potential of silencing miR-652 in a mouse model with established pathological hypertrophy and cardiac dysfunction due to pressure overload. Methods: Mice were subjected to a sham operation (n=10) or transverse aortic constriction (TAC, n=14) for 4 weeks to induce hypertrophy and cardiac dysfunction. Mice were subcutaneously administered a locked nucleic acid (LNA)-antimiR-652 or LNA-control. Cardiac function was assessed by echocardiography before and 8 weeks post treatment, followed by molecular and histological analyses. Results: Expression of miR-652 increased in hearts subjected to pressure overload compared to sham operated mice (2.9 fold, n=3-5, P<0.05), but was silenced in hearts of mice administered LNA-antimiR-652 (95% decrease, n=3-7, P<0.05). In mice subjected to pressure overload, inhibition of miR-652 improved cardiac function (29±1% at 4 weeks post TAC compared to 35±1% post treatment, n=7, P<0.001) and attenuated cardiac hypertrophy. Functional and morphologic improvements in hearts of treated mice were associated with reduced cardiac fibrosis, apoptosis, cardiomyocyte size; decreased B-type natriuretic peptide gene expression; and preserved angiogenesis (all P<0.05, n=4-7/group). Mechanistically, we identified Jagged1, a Notch1 ligand, as a direct target of miR-652 by luciferase assay. Jagged1 and Notch1 mRNA were upregulated in hearts of TAC treated mice (1.2-1.7 fold, n=7, P<0.05). Importantly, chronic knockdown of miR-652 was not associated with any notable toxicity in other tissues. Conclusion: Therapeutic silencing of miR-652 protects the heart against pathological cardiac remodeling and improves heart function via mechanisms that are associated with preserved angiogenesis, decreased fibrosis and upregulation of a miR-652 target, Jagged1. These studies provide the first evidence that targeted inhibition of miR-652 could represent an attractive approach for the treatment of heart failure.

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Established and Emerging Mechanisms in the Pathogenesis of Arrhythmogenic Cardiomyopathy: A Multifaceted Disease

International Journal of Molecular Sciences ◽

10.3390/ijms21176320 ◽

2020 ◽

Vol 21 (17) ◽

pp. 6320

Author(s):

Shanshan Gao ◽

Deepa Puthenvedu ◽

Raffaella Lombardi ◽

Suet Nee Chen

Keyword(s):

Molecular Mechanisms ◽

Molecular Genetic ◽

Autoimmune Response ◽

Arrhythmogenic Cardiomyopathy ◽

Cellular Mechanisms ◽

Paracrine Factors ◽

Epicardial Cells ◽

Genes Encoding ◽

Advanced Stages ◽

Canonical Wnt

Arrhythmogenic cardiomyopathy (ACM) is a heritable myocardial disease that manifests with cardiac arrhythmias, syncope, sudden cardiac death, and heart failure in the advanced stages. The pathological hallmark of ACM is a gradual replacement of the myocardium by fibroadiposis, which typically starts from the epicardium. Molecular genetic studies have identified causal mutations predominantly in genes encoding for desmosomal proteins; however, non-desmosomal causal mutations have also been described, including genes coding for nuclear proteins, cytoskeleton componentsand proteins involved in excitation-contraction coupling. Despite the poor prognosis, currently available treatments can only partially control symptoms and to date there is no effective therapy for ACM. Inhibition of the canonical Wnt/β-catenin pathway and activation of the Hippo and the TGF-β pathways have been implicated in the pathogenesis of ACM. Yet, our understanding of the molecular mechanisms involved in the development of the disease and the cell source of fibroadiposis remains incomplete. Elucidation of the pathogenesis of the disease could facilitate targeted approaches for treatment. In this manuscript we will provide a comprehensive review of the proposed molecular and cellular mechanisms of the pathogenesis of ACM, including the emerging evidence on abnormal calcium homeostasis and inflammatory/autoimmune response. Moreover, we will propose novel hypothesis about the role of epicardial cells and paracrine factors in the development of the phenotype. Finally, we will discuss potential innovative therapeutic approaches based on the growing knowledge in the field.

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Changes in Thyroid Hormone Signaling Mediate Cardiac Dysfunction in the Tg197 Mouse Model of Arthritis: Potential Therapeutic Implications

Journal of Clinical Medicine ◽

10.3390/jcm10235512 ◽

2021 ◽

Vol 10 (23) ◽

pp. 5512

Author(s):

Lydia Ntari ◽

Polyxeni Mantzouratou ◽

Athanasia Katsaouni ◽

Constantinos Pantos ◽

George Kollias ◽

...

Keyword(s):

Thyroid Hormone ◽

Mouse Model ◽

Cardiac Function ◽

P38 Mapk ◽

Cardiac Dysfunction ◽

Systolic Dysfunction ◽

Calcium Handling ◽

Hormone Signaling ◽

Akt Activation ◽

Cardiac Phenotype

Background Rheumatoid Arthritis (RA) patients show a higher risk of heart failure. The present study investigated possible causes of cardiac dysfunction related to thyroid hormone (TH) signaling in a RA mouse model. Methods A TNF-driven mouse model of RA[TghuTNF (Tg197)] was used. Cardiac function was evaluated by echocardiography. SERCA2a and phospholamban protein levels in left ventricle (LV) tissue, thyroid hormone levels in serum, TH receptors in LV and TH-related kinase signaling pathways were measured. T3 hormone was administered in female Tg197 mice. Results We show LV and atrial dilatation with systolic dysfunction in Tg197 animals, accompanied by downregulated SERCA2a. We suggest an interaction of pro-inflammatory and thyroid hormone signaling indicated by increased p38 MAPK and downregulation of TRβ1 receptor in Tg197 hearts. Interestingly, female Tg197 mice showed a worse cardiac phenotype related to reduced T3 levels and Akt activation. T3 supplementation increased Akt activation, restored SERCA2a expression and improved cardiac function in female Tg197 mice. Conclusions TNF overexpression of Tg197 mice results in cardiac dysfunction via p38 MAPK activation and downregulation of TRβ1. Gender-specific reduction in T3 levels could cause the worse cardiac phenotype observed in female mice, while T3 administration improves cardiac function and calcium handling via modified Akt activation.

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Abstract 210: PPARγ Activation Prevents Cardiac Dysfunction in Sepsis via Stimulation of Energy Production

Circulation Research ◽

10.1161/res.111.suppl_1.a210 ◽

2012 ◽

Vol 111 (suppl_1) ◽

Author(s):

Konstantinos Drosatos ◽

Raffay S Khan ◽

Chad M Trent ◽

P Christian Schulze ◽

Shunichi Homma ◽

...

Keyword(s):

Gene Expression ◽

Fatty Acid ◽

Cardiac Function ◽

Cardiac Dysfunction ◽

Lethal Dose ◽

Acid Oxidation ◽

Fatty Acid Transport ◽

Mrna Levels ◽

Pparγ Agonist ◽

Energy Deprivation

Septic cardiac dysfunction has been attributed to either inflammation or suppression of fatty acid oxidation (FAO). We hypothesized that energy deprivation accounts for cardiac dysfunction in lipopolysaccharide (LPS)-induced sepsis. LPS compromised cardiac function, increased cardiac inflammatory markers (interleukin (IL)-1α, IL-6 and tumor necrosis factor (TNF)α) mRNA, and reduced FAO, ATP and FAO-related gene expression: Peroxisome proliferator activating receptor (PPAR)α, cluster of differentiation 36, lipoprotein lipase (LpL), fatty acid transport protein, carnitine palmitoyl-transferase (Cpt)1, PPARγ coactivator (PGC-1)α and PGC-1β in C57BL/6 mice. LC-MS/MS analysis of cardiac lipids showed that total ceramide, which might account for defective FAO and ceramide species were not modulated by LPS. Electron microscopy and ATPase6 DNA levels showed that LPS-treated animals had fewer and smaller cardiac mitochondria. PPARα agonist, WY-14643, did not prevent cardiac dysfunction and suppression of FAO-associated gene expression in LPS-treated mice. In contrast, LPS did not affect cardiac function of mice with cardiomyocyte-specific expression of PPARγ (αMHC-PPARg), although cardiac IL-1α, IL-6 and TNFα mRNA levels were increased. Despite a 77% reduction in PPARα, mRNA levels of FAO-associated genes, such as acyl-CoA oxidase, PGC-1α, PPARδ, Cpt1 increased over 10-fold as compared to saline-treated αMHC-PPARg mice. Similarly, cardiac FAO and ATP content was 2.6 and 5-fold greater in LPS-treated αMHC-PPARγ mice compared to LPS-treated C57BL/6 mice. Moreover, treatment of C57BL/6 mice with LPS and the PPARγ agonist, rosiglitazone, prevented cardiac dysfunction, increased FAO and relevant gene expression, while IL-1α, IL-6 and TNFα mRNA levels increased. Rosiglitazone prevented LPS-mediated reduction of PGC-1α and maintained the number and size of mitochondria. Treatment of C57BL/6 mice with a lethal dose of LPS (15 mg/kg) and repeated doses of rosiglitazone (30mg/kg/day for 72 hours) improved survival, mobility and overall appearance of LPS-treated mice. Thus, PPARγ activation stabilized cardiac energy and prevented cardiac dysfunction and mortality in septic animals despite cardiac inflammation and PPARα downregulation.

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Abstract 365: Ponatinib Triggers Cardiac Inflammation by STAT-3 Dependent Immune Checkpoint Blockade

Circulation Research ◽

10.1161/res.127.suppl_1.365 ◽

2020 ◽

Vol 127 (Suppl_1) ◽

Author(s):

Anand P Singh ◽

Tousif Sultan ◽

Prachi Umbarkar ◽

Qinkun Zhang ◽

Hind Lal

Keyword(s):

Adverse Events ◽

Mouse Model ◽

Cardiac Function ◽

Immune Cells ◽

Cardiac Dysfunction ◽

Kinase Inhibitor ◽

Immune Checkpoint Blockade ◽

Immune Checkpoints ◽

Myocardial Inflammation ◽

Cardiac Inflammation

Background: Ponatinib is a potent anticancer tyrosine kinase inhibitor (TKI) with considerable cardiotoxicity. The manifestation of cardiovascular adverse events, including fatal myocardial infarction and congestive heart failure, has hampered its clinical use. Therefore, a better understanding of the mechanism by which ponatinib exerts cardiotoxicity is urgently warranted to efficiently counteract treatment-related adversities. Methods: Wild type C57BL/6, comorbidity mouse model ApoE -/- , and pressure overload (PO) mouse model were used to investigate the cardiotoxic mechanism of ponatinib. Echocardiography was performed to assess cardiac function. Flow cytometry analysis was performed to assess the dynamics of inflammation. Results: We observed that high-fat diet (HFD) fed ApoE -/- mice develop cardiac dysfunction within 2 weeks of ponatinib treatment. An unbiased RNA-Seq analysis revealed significant upregulation of inflammatory genes (CCR1, CCR5, CCL6, CCL8, CCL9, CXCL4) in ponatinib treated hearts. Since ApoE -/- background, and HFD are known confounder of inflammation signal, we validated this observation in naïve C57BL/6 mice. Despite the lack of cardiac dysfunction in ponatinib treated naïve C57BL/6 mice, comprehensive immune profiling depicted upregulation of myocardial inflammation as evident by infiltrated immune cells (CD45 + TNFα + , CD45 + CD11b + F4/80 + Ly6C + CCR2 + , CD45 + Gal1 + ). Interestingly, we also demonstrated the downregulation of immune checkpoints over T cells (TCRαβ + CTLA4 + , TCRαβ + PD1 + ) in ponatinib treated hearts. Next, in the PO mouse model, ponatinib treated mice showed significant cardiac dysfunction with myocardial inflammation as reflected by increased frequencies of inflammatory parameters (TNFα + , IL1β + , IL6 + , MCP1 + , CXCL9 + ). Mechanistically, we demonstrated that ponatinib potentially suppresses PD-L1 expression over cardiomyocytes via inhibition of STAT3, subsequently leading to immune cells mediated myocardial inflammation. Conclusions: These findings uncover a novel mechanism of ponatinib induced cardiac inflammation leading to adverse cardiac function. It also suggests that strategies to attenuate inflammation may be an effective therapy to prevent ponatinib induced cardiac adverse events.

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Hormone and receptor interplay in the regulation of mosquito lipid metabolism

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1619326114 ◽

2017 ◽

Vol 114 (13) ◽

pp. E2709-E2718 ◽

Cited By ~ 35

Author(s):

Xueli Wang ◽

Yuan Hou ◽

Tusar T. Saha ◽

Gaofeng Pei ◽

Alexander S. Raikhel ◽

...

Keyword(s):

Gene Expression ◽

Lipid Metabolism ◽

Blood Meal ◽

Hormonal Regulation ◽

Luciferase Reporter ◽

Transcript Levels ◽

Genes Encoding ◽

Tightly Coupled ◽

High Level ◽

Lipid Stores

Mosquitoes transmit devastating human diseases because they need vertebrate blood for egg development. Metabolism in female mosquitoes is tightly coupled with blood meal-mediated reproduction, which requires an extremely high level of energy consumption. Functional analysis has shown that major genes encoding for enzymes involved in lipid metabolism (LM) in the mosquito fat bodies are down-regulated at the end of the juvenile hormone (JH)-controlled posteclosion (PE) phase but exhibit significant elevation in their transcript levels during the post-blood meal phase (PBM), which is regulated mainly by 20-hydroxyecdysone (20E). Reductions in the transcript levels of genes encoding triacylglycerol (TAG) catabolism and β-oxidation enzymes were observed to correlate with a dramatic accumulation of lipids in the PE phase; in contrast, these transcripts were elevated significantly and lipid stores were diminished during the PBM phase. The RNAi depletion of Methoprene-tolerant (Met) and ecdysone receptor (EcR), receptors for JH and 20E, respectively, reversed the LM gene expression and the levels of lipid stores and metabolites, demonstrating the critical roles of these hormones in LM regulation. Hepatocyte nuclear factor 4 (HNF4) RNAi-silenced mosquitoes exhibited down-regulation of the gene transcripts encoding TAG catabolism and β-oxidation enzymes and an inability to use lipids effectively, as manifested by TAG accumulation. The luciferase reporter assay showed direct regulation of LM-related genes by HNF4. Moreover, HNF4 gene expression was down-regulated by Met and activated by EcR and Target of rapamycin, providing a link between nutritional and hormonal regulation of LM in female mosquitoes.

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PO-190 Exercise Training Protects Against Cardiac Pathological Remodeling in Myocardial Infarction rats via Improving Mitochondrial Biogenesis

Exercise Biochemistry Review ◽

10.14428/ebr.v1i4.12833 ◽

2018 ◽

Vol 1 (4) ◽

Author(s):

Dandan Jia ◽

Zhenjun Tian

Keyword(s):

Oxidative Stress ◽

Myocardial Infarction ◽

Exercise Training ◽

Cardiac Function ◽

Myocardial Fibrosis ◽

Mitochondrial Biogenesis ◽

Cardiac Dysfunction ◽

Myocardial Apoptosis ◽

The Impact ◽

Pathological Remodeling

Objective Growing evidence suggests that exercise training reverses cardiac pathological remodeling and cardiac dysfunction during myocardial infarction (MI), but the underlying mechanisms have not been fully understood. In this study, we investigated the impact of exercise training on cardiac function, myocardial fibrosis, apoptosis, oxidative stress and mitochondrial biogenesis. Methods Sprague Dawley rats were subjected to MI by permanent ligation of the left anterior descending (LAD) coronary artery or Sham operation. Rats with MI were randomly assigned to sedentary MI group (MI) and MI with exercise training group (MI+EX), and compared to sham-operated group (Sham). Haemodynamics and Masson staining were conducted to evaluate the effect of exercise training on cardiac function and myocardial fibrosis. Myocardial apoptosis, oxidative stress, mitochondrial biogenesis and molecular signaling mechanism were analyzed. Results Exercise training significantly improves cardiac function and mitigates the MI-induced cardiac pathological remodeling. Meanwhile, Exercise training significantly attenuates MI-induced apoptosis, oxidative stress and mitochondrial biogenesis. In addition, activation of PI3K pathway following MI is further induced by exercise training. Conclusions Exercise training protects against MI-induced cardiac dysfunction and pathological remodeling through preventing myocardial apoptosis and oxidative stress, and enhancing mitochondrial biogenesis.

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Silencing CircHIPK3 Sponges miR-93-5p to Inhibit the Activation of Rac1/PI3K/AKT Pathway and Improves Myocardial Infarction-Induced Cardiac Dysfunction

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.645378 ◽

2021 ◽

Vol 8 ◽

Author(s):

Yijin Wu ◽

Min Wu ◽

Jue Yang ◽

Ying Li ◽

Wenying Peng ◽

...

Keyword(s):

Myocardial Infarction ◽

Cardiac Function ◽

Infarct Size ◽

Cardiac Dysfunction ◽

Harmful Effect ◽

Akt Pathway ◽

Circular Rnas ◽

Cerna Network ◽

Myocardial Apoptosis

The ceRNA network involving circular RNAs (circRNAs) is essential in the cardiovascular system. We investigated the underlying ceRNA network involving circHIPK3 in myocardial infarction (MI). After an MI model was established, cardiac function was verified, and myocardial tissue damage in mice with MI was evaluated. A hypoxia model of cardiomyocytes was used to simulate MI in vivo, and the expression of and targeting relationships among circHIPK3, miR-93-5p, and Rac1 were verified. The apoptosis of cardiomyocyte was identified. Gain- and loss-of-functions were performed to verify the ceRNA mechanism. The MI-modeled mice showed cardiac dysfunction and enlarged infarct size. CircHIPK3 was highly expressed in mouse and cell models of MI. Silencing circHIPK3 reduced infarct size, myocardial collagen deposition, and myocardial apoptosis rate and improved cardiac function. CircHIPK3 sponged miR-93-5p, and miR-93-5p targeted Rac1. Overexpression of miR-93-5p inhibited MI-induced cardiomyocyte injury and eliminated the harmful effect of circHIPK3. CircHIPK3 acted as ceRNA to absorb miR-93-5p, thus promoting the activation of the Rac1/PI3K/AKT pathway. We highlighted that silencing circHIPK3 can upregulate miR-93-5p and then inhibit the activation of Rac1/PI3K/Akt pathway, which can improve MI-induced cardiac dysfunction.

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