Myofibroblast Deficiency of LSD1 Alleviates TAC-Induced Heart Failure

2021 ◽  
Author(s):  
Jin-Ling Huo ◽  
Lemin Jiao ◽  
Qi An ◽  
Xiuying Chen ◽  
Yuruo Qi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Remodeling ◽  
Transforming Growth Factor ◽  
Heart Function ◽  
Wild Type Mouse ◽  
Neonatal Rat ◽  
Mouse Heart ◽  
Ang Ii

Rationale: Histone lysine specific demethylase 1 (LSD1) is an important epigenetic anti-tumor drug target, whose inhibitors are currently in phase Ⅰ/Ⅱ clinical trials. However, the potential side effects of LSD1 inhibition in the progress of cardiac remodeling to heart failure remain to be investigated. Objective: To evaluate the roles of myofibroblast- or cardiomyocyte-specific LSD1 deficiency in pressure overload-induced cardiac remodeling. Methods and Results: Adult mouse cardiac fibroblasts (CFs)，neonatal rat cardiac myocytes (NRCMs) and fibroblasts (NRCFs) were isolated, respectively. The myofibroblast-specific and cardiomyocyte-specific LSD1 inducible knockout mice were then generated. We found that LSD1 was increased not only in human DCM (dilated cardiomyopathy) hearts, but also in wild type mouse heart homogenates and isolated CFs, following 20 weeks of transverse aortic constriction (TAC). The upregulation of LSD1 was also observed in Ang II-treated NRCFs, which was reversed by LSD1 silence or its activity inhibition by ORY-1001. These findings suggested a potential involvement of LSD1 in cardiac remodeling. Importantly, myofibroblast-specific LSD1 inducible knockout in vivo significantly alleviated systolic dysfunction, cardiac hypertrophy and fibrosis, following 6 and 20 weeks of TAC. Mechanistically, through RNA-sequencing and the following western blot analysis, we found that loss of LSD1 in Ang II-induced myofibroblasts not only inhibited the intracellular upregulation of transforming growth factor β1 (TGFβ1), its downstream effectors Smad2/3 phosphorylation, as well as the phosphorylation of p38, ERK1/2 and JNK, but also reduced the supernatant TGFβ1 secretion, which then decreased myocyte hypertrophy in the indirect co-culture model. On the other hand, cardiomyocyte-specific LSD1 inducible knockout in vivo triggered the reprogramming of fetal genes, mild cardiac hypertrophy and dysfunction under both basal and stressed conditions. Conclusions: Our findings, for the first time, implicate that myofibroblast-specific LSD1 deletion attenuates TAC-induced cardiac remodeling and improves heart function, suggesting that LSD1 is a potential therapeutic target for late stage heart failure.

scholarly journals LncRNA4930473A02Rik promotes cardiac hypertrophy by regulating TCF7 via sponging miR-135a in mice

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Jing Ren ◽  
Hanping Qi ◽  
Chao Song ◽  
Lina Ba ◽  
Renling Liu ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Protective Effect ◽  
Heart Function ◽  
Luciferase Assay ◽  
Mouse Heart ◽  
Ang Ii ◽  
Downstream Target ◽  
Underlying Mechanisms

AbstractCardiac hypertrophy is a common pathological change accompanied by various cardiovascular diseases; however, its underlying mechanisms remain elusive. Mounting evidence indicates that long non-coding RNAs (lncRNAs) are novel transcripts involved in regulating multiple biological processes. However, little is known about their role in regulating cardiac hypertrophy. This study revealed a novel lncRNA4930473A02Rik (abbreviated as lncRNAA02Rik), which showed considerably increased expression in hypertrophic mouse hearts in vivo and angiotensin-II (Ang-II)-induced hypertrophic cardiomyocytes in vitro. Notably, lncRNAA02Rik knockdown partly ameliorated Ang-II induced hypertrophic cardiomyocytes in vitro and hypertrophic mouse heart function in vivo, whereas lncRNAA02Rik overexpression promoted cardiac hypertrophy in vitro. Furthermore, lncRNAA02Rik acted as a competing endogenous RNA by sponging miR-135a, while forced expression of lncRNAA02Rik could repress its activity and expression. Furthermore, forcing miR-135a overexpression exerted a significant protective effect against cardiac hypertrophy by inhibiting the activity of its downstream target TCF7, a critical member of Wnt signaling, and the protective effect could be reversed by AMO-135a. Luciferase assay showed direct interactions among lncRNAA02Rik, miR-135a, and TCF7. Altogether, our study demonstrated that lncRNAA02Rik upregulation could promote cardiac hypertrophy development via modulating miR-135a expression levels and TCF7 activity. Therefore, lncRNAA02Rik inhibition might be considered as a novel potential therapeutic strategy for cardiac hypertrophy.

scholarly journals Physical Activity and Inhibition of ACE Additively Modulate ACE/ACE-2 Balance in Heart Failure in Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Urszula Tyrankiewicz ◽  
Mariola Olkowicz ◽  
Piotr Berkowicz ◽  
Magdalena Jablonska ◽  
Ryszard T. Smolenski ◽  
...  
Keyword(s):  
Physical Activity ◽  
Heart Failure ◽  
Heart Function ◽  
Combined Treatment ◽  
Training Group ◽  
Cardiac Performance ◽  
Angiotensin Converting Enzyme Inhibition ◽  
Ang Ii ◽  
Spontaneous Physical Activity

Angiotensin-converting enzyme inhibition (ACE-I) and physical activity favorably modulate the ACE/ACE-2 balance. However, it is not clear whether physical activity and ACE-I could synergistically modulate ACE/ACE-2 balance in the course of heart failure (HF). Here, we studied the effects of combined spontaneous physical activity and ACE-I–based treatment on angiotensin (Ang) pattern and cardiac function in a mouse model of HF (Tgαq*44). Tgαq*44 mice with advanced HF (at the age of 12 months) were running spontaneously in a running wheel (exercise training group, ExT) and/or were treated with ACE inhibitor (ACE-I, perindopril, 10 mg/kg) for 2 months. Angiotensin profile was characterized by an LC-MS/MS-based method. The cardiac performance was assessed in vivo by MRI. Ang-(1–7)/Ang II ratio in both plasma and the aorta was significantly higher in the combined treatment group than the ACE-I group or ExT alone, suggesting the additive favorable effects on ACE-2/Ang-(1–7) and ACE/Ang II axes’ balance induced by a combination of ACE-I with ExT. The basal cardiac performance did not differ among the experimental groups of Tgαq*44 mice. We demonstrated additive changes in ACE/ACE-2 balance in both plasma and the aorta by spontaneous physical activity and ACE-I treatment in Tgαq*44 mice. However, these changes did not result in an improvement of failing heart function most likely because the disease was at the end-stage. Ang-(1–7)/Ang II balance represents a valuable biochemical end point for monitoring therapeutic intervention outcome in heart failure.

scholarly journals Myricetin Alleviates Pathological Cardiac Hypertrophy via TRAF6/TAK1/MAPK and Nrf2 Signaling Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Hai-han Liao ◽  
Nan Zhang ◽  
Yan-yan Meng ◽  
Hong Feng ◽  
Jing-jing Yang ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Pressure Overload ◽  
Mapk Signaling ◽  
Neonatal Rat ◽  
Mouse Heart ◽  
Pathological Cardiac Hypertrophy ◽  
Pathological Hypertrophy ◽  
Nrf2 Signaling Pathway

Myricetin (Myr) is a common plant-derived polyphenol and is well recognized for its multiple activities including antioxidant, anti-inflammation, anticancer, and antidiabetes. Our previous studies indicated that Myr protected mouse heart from lipopolysaccharide and streptozocin-induced injuries. However, it remained to be unclear whether Myr could prevent mouse heart from pressure overload-induced pathological hypertrophy. Wild type (WT) and cardiac Nrf2 knockdown (Nrf2-KD) mice were subjected to aortic banding (AB) surgery and then administered with Myr (200 mg/kg/d) for 6 weeks. Myr significantly alleviated AB-induced cardiac hypertrophy, fibrosis, and cardiac dysfunction in both WT and Nrf2-KD mice. Myr also inhibited phenylephrine- (PE-) induced neonatal rat cardiomyocyte (NRCM) hypertrophy and hypertrophic markers’ expression in vitro. Mechanically, Myr markedly increased Nrf2 activity, decreased NF-κB activity, and inhibited TAK1/p38/JNK1/2 MAPK signaling in WT mouse hearts. We further demonstrated that Myr could inhibit TAK1/p38/JNK1/2 signaling via inhibiting Traf6 ubiquitination and its interaction with TAK1 after Nrf2 knockdown in NRCM. These results strongly suggested that Myr could attenuate pressure overload-induced pathological hypertrophy in vivo and PE-induced NRCM hypertrophy via enhancing Nrf2 activity and inhibiting TAK1/P38/JNK1/2 phosphorylation by regulating Traf6 ubiquitination. Thus, Myr might be a potential strategy for therapy or adjuvant therapy for malignant cardiac hypertrophy.

Abstract 77: MiR-125b Regulates Myofibroblast Transition and Cardiac Fibrosis

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Varun Nagpal ◽  
Rahul Rai ◽  
Aaron T Place ◽  
Asish K Ghosh ◽  
Douglas E Vaughan
Keyword(s):  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Primary Cultures ◽  
Locked Nucleic Acid ◽  
Mouse Heart ◽  
Ang Ii ◽  
Fibroblast Proliferation ◽  
Systemic Delivery ◽  
Critical Determinant

Transforming growth factor-β (TGF-β)-induced fibroblast-to-myofibroblast transition (FMT) is a critical determinant of cardiac fibrosis. However, the contribution of microRNAs leading to TGF-β-induced FMT and cardiac fibrosis are not well-understood. Our results elucidate that blocking the canonical TGF-β pathway protects from FMT in primary cultures of human cardiac fibroblasts and that miR-125b is significantly upregulated during cardiac FMT. Furthermore, we observed significant upregulation of miR-125b in fibrotic human myocardium and two murine models of cardiac fibrosis. Importantly, we discovered that miR-125b is sufficient to induce cardiac FMT. In contrast, the knockdown of miR-125b using an antagomir approach attenuated TGF-β-induced FMT. In silico analysis and biochemical analysis revealed that miR-125b directly targets multiple anti-fibrotic mediators including p53 and apelin. In addition, miR-125b also plays a potent role in the regulation of fibroblast proliferation, an important cause of cardiac fibrosis. Finally, miR-125b was successfully inhibited in vivo by the systemic delivery of locked nucleic acid (LNA) targeted against miR-125b both in the presence and absence of Angiotensin II (Ang II). These results demonstrated that LNA-125b protected against Ang II-induced proliferation and fibrosis in the mouse heart in vivo. We conclude that TGF-β-induced miR-125b is an important regulator of both fibroblast proliferation and FMT, and miR-125b inhibits key anti-fibrotic mediators to promote cardiac fibrosis. We propose that miR-125b may serve as a novel therapeutic target for the preventative therapy for fibrosis.

scholarly journals Citri Reticulatae Pericarpium Alleviates Postmyocardial Infarction Heart Failure by Upregulating Pparγ Expression

2021 ◽  
Author(s):  
Mengli Chen ◽  
Hongyan Zhu ◽  
Qingqing Zhu ◽  
Xiaodong Wu ◽  
Yufei Zhou ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Molecular Mechanisms ◽  
Systolic Function ◽  
Tunel Staining ◽  
Mouse Heart ◽  
Coronary Artery Ligation ◽  
Traditional Chinese Herbal Medicine

Abstract PurposeHeart failure after myocardial infarction (MI) is the leading cause of death worldwide. Citri Reticulatae Pericarpium (CRP) is a traditional Chinese herbal medicine that has been used in the clinic for centuries. In this study, we aimed to investigate the roles of CRP in cardiac remodeling and heart failure after MI, as well as the molecular mechanisms involved.MethodsMale C57BL/6 mice aged 8 weeks were subjected to coronary artery ligation to mimic the clinical situation in vivo. Echocardiography was used to assess the systolic function of the mouse heart. Masson trichrome staining and Wheat germ agglutinin (WGA) staining were utilized to determine the fibrotic area and cross-sectional area of the mouse heart, respectively. Cardiomyocytes and fibroblasts were isolated from neonatal rats aged 0–3 days in vitro using enzyme digestion. TUNEL staining and EdU staining were performed to evaluate apoptosis and proliferation, respectively. Gene expression changes were analyzed by qRT–PCR, and protein expression changes were assessed by Western blotting.ResultsOur findings revealed that CRP attenuated cardiac hypertrophy, fibrosis and apoptosis and alleviated heart failure after MI in vivo. Furthermore, CRP mitigated cardiomyocyte apoptosis and fibroblast proliferation and differentiation into myofibroblasts. In addition, the PPARγ inhibitor T0070907 completely abolished the abovementioned beneficial effects of CRP, and the PPARγ activator rosiglitazone failed to further ameliorate cardiac apoptosis and fibrosis in vitro.ConclusionCRP alleviates cardiac hypertrophy, fibrosis, and apoptosis and can ameliorate heart failure after MI via activation of PPARγ.

Abstract 13402: FHL-1 Contributes to and Colocalizes With Titin in Cardiac Hypertrophy

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Nesrine El-Bizri ◽  
Jing Liu ◽  
Rachel Matt ◽  
Rugmani P Iyer ◽  
Girija Raman ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Diastolic Dysfunction ◽  
Neonatal Rat ◽  
In Vivo Studies ◽  
Myoblast Differentiation ◽  
Mrna Levels ◽  
Tissue Samples ◽  
Diastolic Compliance

Increased myocardial stiffness is a hallmark of impaired diastole in heart failure (HF). Hypo-phosphorylation of the N2B unique sequence (N2Bus) of titin (TTN), a giant myofilament protein, increases passive tension leading to diastolic dysfunction in HF. Enhancing the altered N2Bus phosphorylation improves cardiac stiffness and function. FHL-1, an interacting protein potentially modulating N2Bus phosphorylation is increased in HF. FHL-1 knockout mice display blunted cardiac hypertrophy and improved diastolic compliance in response to pressure-overload by transverse aortic constriction, TAC. FHL-1 also regulates skeletal muscle hypertrophy. We hypothesize that FHL-1 contributes to cardiac hypertrophy and colocalizes/interacts with TTN in heart failure. In house IHC data showed site-specific N2Bus hypo-phosphorylation at S4099, S4010 and S4185 in human HCM and/or DCM tissue samples. Longitudinal in-vivo studies showed that FHL-1 and cardiac hypertrophy markers genes were increased in left ventricles (LV) of TAC mice using RNA-seq. A persistently enhanced FHL-1 protein expression by immunoblotting and mass spectrometry strongly correlated with LV hypertrophy at 1, 4, and 6 weeks post-TAC. In addition, LV hypertrophy correlated negatively with function (fractional shortening). Increases in FHL-1 and hypertrophy markers mRNA levels were confirmed by RT-qPCR in neonatal rat ventricular myocytes (NRVM) under phenylephrine (PE) and endothelin-1 (ET-1) induced hypertrophy. Under similar conditions, FHL-1 protein levels were increased by immunofluorescence (IF) in cytoplasmic, perinuclear and nuclear regions of NRVM. Colocalization of phospho-TTN and FHL-1 was observed in NRVM and was enhanced under PE- and ET-1 induced hypertrophy. IF studies in human skeletal myotubes showed that FHL-1 expression was increased during myoblast differentiation and IGF1-E3R induced hypertrophy. Preliminary data using Microscale Thermophoresis showed binding affinity between N2Bus and FHL-1 proteins. Our studies show that FHL-1 contributes to hypertrophy in addition to N2B hypo-phosphorylation status contributing to diastolic dysfunction in HF. Targeting FHL-1 and TTN can be a potential strategy to improve diastolic compliance in HF.

Abstract 185: Tripartite Motif E3 Ubiquitin Ligase Family Proteins Regulate Intracellular Signaling During the Progression of Heart Failure

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Jenna Alloush ◽  
Eric X Beck ◽  
Sayak Bhattacharya ◽  
Zhaobin Xu ◽  
Liubov Guschina ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Intracellular Signaling ◽  
Heart Function ◽  
Major Complication ◽  
Akt Signaling ◽  
Mouse Heart ◽  
Pi3k Signaling ◽  
Signaling Mechanisms ◽  
Tripartite Motif

Heart failure is a major complication of cardiovascular disease that frequently involves initial cardiac hypertrophy that provides transient compensation for decreased heart function. Eventually, decompensation leads to compromised cardiac structure and progression into heart failure. Investigation of the downstream effector pathways for these growth factors has identified molecules involved in the progression of cardiac hypertrophy and heart failure, including phosphoinositide 3-kinase (PI3K) and Akt (Protein Kinase B). MG53, a tripartite motif (TRIM) protein family member designated as TRIM72, is highly expressed in skeletal and cardiac muscle and is known to have cardioprotective effects through modulation of PI3K signaling mechanisms. It is essential for the activation of PI3K-mediated intracellular signaling in cardiomyocytes and TRIM72 overexpression is sufficient to induce PI3K signaling. As TRIM72 regulates PI3K signaling it may play a role in regulation of heart failure, which is supported by our findings that TRIM72 levels increase in the failing mouse heart. Our recent studies also show that TRIM72 can form heterodimers with other members of the TRIM family proteins that contains approximately 70 different members in the human genome. Many TRIM family proteins are known to act as E3 ubiquitin ligases that target the ubiquitin proteasome to particular proteins. Through this activity, TRIM72 homodimers and heterodimers can resolve specific substrates that can modulate aspects of the PI3K/Akt signaling cascade. Our recent studies have resolved multiple binding partners for TRIM72 in the TRIM family that are co-regulated during heart failure. Resolving the target substrates of the heterodimers formed by these various family members and determining their role in regulating PI3K/Akt signaling mechanisms during cardiac hypertrophy will be further defined as our studies continue.

Abstract 419: Stim1 is Associated With Calcium Microdomains That are Required for Myofilament Remodeling and Signaling During Cardiac Hypertrophy

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Cory Parks ◽  
Ryan D Sullivan ◽  
Salvatore Mancarella
Keyword(s):  
Cardiac Hypertrophy ◽  
Heart Function ◽  
Cardiac Contractility ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Excitable Cells ◽  
Rat Cardiomyocytes ◽  
Cell Contractility

Stromal Interaction Protein 1 (STIM1) is the intracellular component of the store operated calcium channels. It is a ubiquitous Ca2+ sensor, prevalently located in the sarcoplasmic reticulum. In non-excitable cells, STIM1 is a key element in the generation of Ca2+signals that lead to gene expression and cell proliferation. A growing body of literature now suggests that STIM1 is important for normal heart function and plays a key role in the development of pathological cardiac hypertrophy. However, the precise mechanisms involving STIM1 and the Ca2+ signaling in excitable cells are not clearly established. We show that in neonatal rat cardiomyocytes, the spatial properties of STIM1-dependent Ca2+ signals determine restricted Ca2+ microdomains that regulate myofilaments remodeling and spatially segregated activation of pro-hypertrophic factors. Indeed, in vivo data obtained from an inducible cardiac restricted STIM1 knockout mouse, exhibited left ventricular dilatation associated with reduced cardiac contractility, which was corroborated by impaired single cell contractility. Furthermore, mice lacking STIM1 showed less adverse structural remodeling in response to pathological pressure overload-induced cardiac hypertrophy (transverse aortic constriction, TAC). We further show that the Ca2+ pool associated with STIM1 is the ON switch for extracellular signal-regulated kinase (ERK1/2)-mediated cytoplasm to nucleus signaling. These results highlight how STIM1-dependent Ca2+ microdomains have a major impact on intracellular Ca2+ homeostasis, cytoskeletal remodeling, signaling and cardiac function, even when excitation-contraction coupling is present.

scholarly journals STING protects against cardiac dysfunction and remodelling by blocking autophagy

2021 ◽  
Author(s):  
Rui Xiong ◽  
Ning Li ◽  
Wei Wang ◽  
Bo Wang ◽  
Wenyang Jiang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Protein Expression ◽  
Cardiac Fibroblasts ◽  
Cardiac Remodelling ◽  
Ang Ii ◽  
Mrna And Protein Expression

Abstract Background Heart failure, which is characterized by cardiac remodelling, is one of the most common chronic diseases in the aged. Stimulator of interferon genes (STING) acts as an indispensable molecule modulating immune response and inflammation in many diseases. However, the effects of STING on cardiomyopathy, especially cardiac remodelling are still largely unknown. This study was designed to investigate whether STING could affect cardiac remodelling and to explore the potential mechanisms. Methods In vivo, aortic binding (AB) surgery was performed to construct the mice model of cardiac remodelling. A DNA microinjection system was used to trigger STING overexpression in mice. The STING mRNA and protein expression levels in mice heart were measured, and the cardiac hypertrophy, fibrosis, inflammation and cardiac function were also evaluated. In vitro, cardiomyocytes stimulated by Ang II and cardiac fibroblasts stimulated by TGF-β to performed to further study effects of STING on cardiac hypertrophy and fibroblast. In terms of mechanisms, the level of autophagy was detected in mice challenged with AB. Rapamycin, a canonical autophagy inducer, intraperitoneal injected into mice to study possible potential pathway. Results In vivo, the STING mRNA and protein expression levels in mice heart challenged with AB for 6 weeks were significantly increased. STING overexpression significantly mitigated cardiac hypertrophy, fibrosis and inflammation, apart from improving cardiac function. In vitro, experiments further disclosed that STING overexpression in cardiomyocytes induced by Ang II significantly inhibited the level of cardiomyocyte cross-section area and the ANP mRNA. Meanwhile, TGF-β-induced the increase of α-SMA content and collagen synthesis in cardiac fibroblasts could be also blocked by STING overexpression. In terms of mechanisms, mice challenged with AB showed higher level of autophagy compared with the normal mice. However, STING overexpression could reverse the activation of autophagy triggered by AB. Rapamycin, a canonical autophagy inducer, offset the cardioprotective effects of STING in mice challenged with AB. Finally, further experiments unveiled that STING may inhibit autophagy by phosphorylating ULK1 on serine757. Conclusions STING may prevent cardiac remodelling induced by pressure overload by inhibiting autophagy, which could be a promising therapeutic target in heart failure.

scholarly journals LCZ696 Ameliorates Oxidative Stress and Pressure Overload-Induced Pathological Cardiac Remodeling by Regulating the Sirt3/MnSOD Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-15
Author(s):  
Shi Peng ◽  
Xiao-feng Lu ◽  
Yi-ding Qi ◽  
Jing Li ◽  
Juan Xu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Pressure Overload ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Rat Cardiomyocytes ◽  
Pathological Cardiac Hypertrophy

Aims. We aimed to investigate whether LCZ696 protects against pathological cardiac hypertrophy by regulating the Sirt3/MnSOD pathway. Methods. In vivo, we established a transverse aortic constriction animal model to establish pressure overload-induced heart failure. Subsequently, the mice were given LCZ696 by oral gavage for 4 weeks. After that, the mice underwent transthoracic echocardiography before they were sacrificed. In vitro, we introduced phenylephrine to prime neonatal rat cardiomyocytes and small-interfering RNA to knock down Sirt3 expression. Results. Pathological hypertrophic stimuli caused cardiac hypertrophy and fibrosis and reduced the expression levels of Sirt3 and MnSOD. LCZ696 alleviated the accumulation of oxidative reactive oxygen species (ROS) and cardiomyocyte apoptosis. Furthermore, Sirt3 deficiency abolished the protective effect of LCZ696 on cardiomyocyte hypertrophy, indicating that LCZ696 induced the upregulation of MnSOD and phosphorylation of AMPK through a Sirt3-dependent pathway. Conclusions. LCZ696 may mitigate myocardium oxidative stress and apoptosis in pressure overload-induced heart failure by regulating the Sirt3/MnSOD pathway.

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