A microfluidic platform for the high-throughput study of pathological cardiac hypertrophy

Bakuchiol (Bak), a monoterpene phenol isolated from the seeds of Psoralea corylifolia, has been widely used to treat a large variety of diseases in both Indian and Chinese folkloric medicine. However, the effects of Bak on cardiac hypertrophy remain unclear. Therefore, the present study was designed to determine whether Bak could alleviate cardiac hypertrophy. Mice were subjected to aortic banding (AB) to induce cardiac hypertrophy model. Bak of 1 ml/100 g body weight was given by oral gavage once a day from 1 to 8 weeks after surgery. Our data demonstrated for the first time that Bak could attenuate pressure overload-induced cardiac hypertrophy and could attenuate fibrosis and the inflammatory response induced by AB. The results further revealed that the effect of Bak on cardiac hypertrophy was mediated by blocking the activation of the NF-κB signaling pathway. In vitro studies performed in neonatal rat cardiomyocytes further proved that the protective effect of Bak on cardiac hypertrophy is largely dependent on the NF-κB pathway. Based on our results, Bak shows profound potential for its application in the treatment of pathological cardiac hypertrophy, and we believe that Bak may be a promising therapeutic candidate to treat cardiac hypertrophy and heart failure.

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Abstract 026: Role of Tank in the Regulation of Pathological Cardiac Hypertrophy

Hypertension ◽

10.1161/hyp.68.suppl_1.026 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Hongliang Li ◽

Peng Zhang

Keyword(s):

Cardiac Hypertrophy ◽

Cardiac Dysfunction ◽

Pressure Overload ◽

Adaptor Protein ◽

Negative Regulator ◽

Akt Inhibitor ◽

Aortic Banding ◽

Pathological Cardiac Hypertrophy

TRAF associated NF-κB activator (TANK) is adaptor protein which was identified as a negative regulator of TRAF-, TBK1- and IKKi-mediated signal transduction through its interaction with them. Besides its important roles in the regulation of immune response, it has been reported that TANK contributes to the development of autoimmune nephritis and osteoclastogenesis. However, its functions in cardiovascular diseases especially cardiac hypertrophy is largely unknown. In the present study, we interestingly observed that TNAK expression is increased by 240% in human hypertrophic cardiomyopathy(HCM)tissue and 320% in mouse hypertrophic heart after aortic banding (AB), indicating that TANK may be involved in the pathogenesis of this diseases. Subsequently, cardiac-specific TANK knockout (TANK-KO) and transgenic(TANK-TG)mice were generated and subjected to AB for 4 to 8 weeks. Our results demonstrated that TANK deficiency prevented against cardiac hypertrophy and fibrosis induced by pressure overload,as evidenced by that the cardiomyocytes enlargement and fibrosis formation was reduced by about 34% and 43% compared with WT mice, respectively. Conversely, TANK-TG mice showed an aggravated effect on cardiac hypertrophy in response to pressure overload with 36% and 47% increase of cardiomyocytes enlargement and fibrosis formation compared with non-transgenic mice. More importantly, in vitro experiments further revealed that TANK overexpression which was mediated by adenovirus in the cardiomyocytes dramatically increased the cell size and the expression of hypertrophic markers, whereas TANK knockdown had an opposite function. Mechanistically, we discovered that AKT signaling was activated (230%) in the hearts of TANK-TG mice, while being greatly reduced in TNAK-KO hearts after aortic banding. Moreover, blocking AKT/GSK3β signaling with a pharmacological AKT inhibitor reversed cardiac dysfunction of TANK-TG mice. Collectively, our data show that TNAK acts as a novel regulator of pathological cardiac hypertrophy and may be a promising therapeutic targets.

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TANK Promotes Pressure Overload Induced Cardiac Hypertrophy via Activating AKT Signaling Pathway

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.687540 ◽

2021 ◽

Vol 8 ◽

Author(s):

Yanan Pang ◽

Minglu Ma ◽

Dong Wang ◽

Xun Li ◽

Li Jiang

Keyword(s):

Transgenic Mice ◽

Cardiac Hypertrophy ◽

Knockout Mice ◽

Pressure Overload ◽

Akt Signaling ◽

Control Group ◽

Akt Inhibitor ◽

Aortic Banding ◽

Pathological Cardiac Hypertrophy

Background: TANK (TRAF family member associated NF-κB activator) acts as a member of scaffold proteins participated in the development of multiple diseases. However, its function in process of cardiac hypertrophy is still unknown.Methods and Results: In this study, we observed an increased expression of TANK in murine hypertrophic hearts after aortic banding, suggesting that TANK may be involved in the pathogenesis of cardiac hypertrophy. We generated cardiac-specific TANK knockout mice, and subsequently subjected to aortic banding for 4–8 weeks. TANK knockout mice showed attenuated cardiac hypertrophy and dysfunction compared to the control group. In contrast, cardiac-specific TANK transgenic mice showed opposite signs. Consistently, in vitro experiments revealed that TANK knockdown decreased the cell size and expression of hypertrophic markers. Mechanistically, AKT signaling was inhibited in TANK knockout mice, but activated in TANK transgenic mice after aortic banding. Blocking AKT signaling with a pharmacological AKT inhibitor alleviated the cardiac hypertrophy and dysfunction in TANK transgenic mice.Conclusions: Collectively, we identified TANK accelerates the progression of pathological cardiac hypertrophy and is a potential therapeutic target.

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

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/6304058 ◽

2019 ◽

Vol 2019 ◽

pp. 1-14 ◽

Cited By ~ 4

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.

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Increased afterload induces pathological cardiac hypertrophy: a new in vitro model

Basic Research in Cardiology ◽

10.1007/s00395-012-0307-z ◽

2012 ◽

Vol 107 (6) ◽

Cited By ~ 84

Author(s):

Marc N. Hirt ◽

Nils A. Sörensen ◽

Lena M. Bartholdt ◽

Jasper Boeddinghaus ◽

Sebastian Schaaf ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

In Vitro Model ◽

Pathological Cardiac Hypertrophy ◽

Vitro Model

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Novel PGC-1α/ATF5 Axis Partly Activates UPRmt and Mediates Cardioprotective Role of Tetrahydrocurcumin in Pathological Cardiac Hypertrophy

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/9187065 ◽

2020 ◽

Vol 2020 ◽

pp. 1-21

Author(s):

Bing Zhang ◽

Yanzhen Tan ◽

Zhengbin Zhang ◽

Pan Feng ◽

Wenyuan Ding ◽

...

Keyword(s):

Oxidative Stress ◽

Cardiac Hypertrophy ◽

Test Group ◽

Neonatal Rat ◽

Activation Mechanism ◽

Cardiomyocyte Hypertrophy ◽

Control Group ◽

Pathological Cardiac Hypertrophy

Mitochondrial unfolding protein response (UPRmt) effectively resists the pathological cardiac hypertrophy and improves the mitochondrial function. However, the specific activation mechanism and drugs that can effectively activate UPRmt in the cardiac muscle are yet to be elucidated. The aim of this study was to determine the regulation role of UPRmt on preventing pathological cardiac hypertrophy by tetrahydrocurcumin (THC) and explore its underlying molecular mechanism. Male C57BL/6J wild-type (WT) mice were divided into a control group and subjected to sham treatment for 4 weeks, and a test group which was subjected to transverse aortic constriction (TAC) surgery. Animals in the control and test group were orally administered THC (50 mg/kg) for 4 weeks after TAC procedure; an equivalent amount of saline was orally administered in the control sham-treated group and the TAC group. Subsequently, oxidative stress and UPRmt markers were assessed in these mice, and cardiac hypertrophy, fibrosis, and cardiac function were tested. Small interfering RNA (siRNA) targeting proliferator-activated receptor-gamma coactivator (PGC)-1α and activating transcription factor 5 (ATF5) were used to determine the UPRmt activation mechanism. THC supplement partly upregulated UPRmt effectors and inhibited TAC-induced oxidative stress compared with TAC-operated WT mice, thereby substantially attenuating contractile dysfunction, cardiac hypertrophy, and fibrosis. Furthermore, PGC-1α knockdown blunted the UPRmt activation and the cardioprotective role of THC. The interaction between PGC-1α and ATF5 was tested in neonatal rat cardiac myocytes under normal conditions. The results showed that PGC-1α was an upstream effector of ATF5 and partly activated UPRmt. In vitro, phenylephrine- (PE-) induced cardiomyocyte hypertrophy caused ATF5 upregulating rather than downregulating corresponding to the downregulation of PGC-1α. The PGC-1α/ATF5 axis mediated the UPRmt activation and stress-resistance role of THC in vitro. Collectively, the present study provides the first evidence that PGC-1 and ATF5 can form a signaling axis to partly activate UPRmt that mediates the cardioprotective role of THC in pathological cardiac hypertrophy.

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Cullin-associated and neddylation-dissociated 1 protein (CAND1) governs cardiac hypertrophy and heart failure partially through regulating calcineurin degradation

10.21203/rs.3.rs-333521/v1 ◽

2021 ◽

Author(s):

Zhenwei Pan ◽

Xingda Li ◽

Yang Zhang ◽

Yue Zhao ◽

Yang Zhou ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Hypertrophy ◽

Protein Level ◽

Substrate Protein ◽

Pathological Cardiac Hypertrophy ◽

Promising Therapeutic Target ◽

Specific Proteins ◽

Related Proteins

Abstract Pathological cardiac hypertrophy is a process characterized by significant disturbance of protein turnover. Cullin-associated and Neddylation-dissociated 1 (CAND1) acts as a coordinator to modulate substrate protein degradation by promoting the formation of specific cullin-based ubiquitin ligase 3 complex in response to the accumulation of specific proteins, which thereby maintains the normal protein homeostasis. However, whether CAND1 titrates the degradation of hypertrophic related proteins and manipulates cardiac hypertrophy remains unknown. In this study, we found that the protein level of CAND1 was increased in the heart tissues from heart failure (HF) patients and TAC mice. CAND1-KO+/- aggravated TAC-induced cardiac hypertrophic phenotypes; in contrast, CAND1-Tg attenuated the maladaptive cardiac remodeling. At the protein level, CAND1 overexpression downregulated, whereas CAND1-KO+/- or knockdown upregulated the expression of calcineurin, a critical pro-hypertrophic protein at both in vivo and in vitro conditions. Mechanistically, CAND1 overexpression favored, whilst CAND1 knockdown blocked the assembly of Cul1/atrogin1/calcineurin complex, an E3 that renders the ubiquitination and degradation of calcineurin. It turned out that calcineurin ubiquitination was suppressed by CAND1 knockdown, but enhanced by CAND1 overexpression. In addition, overexpression of truncated calcineurin that cannot be recognized by atrogin1 abrogated the antihypertrophic effects of CAND1. Notably, CAND1 deficiency-induced hypertrophic phenotypes were partially rescued by knockdown of calcineurin, and application of exogenous CAND1 prevented TAC-induced cardiac hypertrophy and heart failure. In conclusion, CAND1 exerts a protective effect against cardiac hypertrophy and heart failure partially by inducing the degradation of calcineurin. CAND1 represents a novel, promising therapeutic target for cardiac hypertrophy and heart failure. Keywords: CAND1; heart failure; calcineurin; ubiquitination; cullin1

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Amlexanox and Forskolin Prevents Isoproterenol-Induced Cardiomyopathy by Subduing Cardiomyocyte Hypertrophy and Maladaptive Inflammatory Responses

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.719351 ◽

2021 ◽

Vol 9 ◽

Author(s):

Gabriel Komla Adzika ◽

Hongjian Hou ◽

Adebayo Oluwafemi Adekunle ◽

Ruqayya Rizvi ◽

Seyram Yao Adzraku ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Troponin I ◽

Inflammatory Responses ◽

Myocardial Hypertrophy ◽

Left Ventricular ◽

Cardiomyocyte Hypertrophy ◽

Myocardial Inflammation ◽

Treatment Interventions ◽

Pathological Cardiac Hypertrophy

Chronic catecholamine stress (CCS) induces the occurrence of cardiomyopathy—pathological cardiac hypertrophy (PCH), which is characterized by left ventricular systolic dysfunction (LVSD). Recently, mounting evidence has implicated myocardial inflammation in the exacerbation of pathological cardiac remodeling. However, there are currently no well-defined treatment interventions or regimes targeted at both the attenuation of maladaptive myocardial hypertrophy and inflammation during CCS to prevent PCH. G protein-coupled receptor kinase 5 (GRK5) and adenylyl cyclases (ACs)-cAMP mediates both cardiac and inflammatory responses. Also, GRK5 and ACs are implicated in stress-induced LVSD. Herein, we aimed at preventing PCH during CCS via modulating adaptive cardiac and inflammatory responses by inhibiting GRK5 and/or stimulating ACs. Isoproterenol-induced cardiomyopathy (ICM) was modeled using 0.5 mg/100 g/day isoproterenol injections for 40 days. Alterations in cardiac and inflammatory responses were assessed from the myocardia. Similarities in the immunogenicity of cardiac troponin I (cTnI) and lipopolysaccharide under CCS were assessed, and Amlexanox (35 μM/ml) and/or Forskolin (10 μM/ml) were then employed in vitro to modulate adaptive inflammatory responses by inhibiting GRK5 or activating ACs-cAMP, respectively. Subsequently, Amlexanox (2.5 mg/100 g/day) and/or Forskolin (0.5 mg/100 g/day) were then translated into in vivo during CCS to modulate adaptive cardiac and inflammatory responses. The effects of Amlexanox and Forskolin on regulating myocardial systolic functions and inflammatory responses during CCS were ascertained afterward. PCH mice had excessive myocardial hypertrophy, fibrosis, and aggravated LVSD, which were accompanied by massive CD68+ inflammatory cell infiltrations. In vitro, Forskolin-AC/cAMP was effective than Amlexanox-GRK5 at downregulating proinflammatory responses during stress; nonetheless, Amlexanox and Forskolin combination demonstrated the most efficacy in modulating adaptive inflammatory responses. Individually, the translated Amlexanox and Forskolin treatment interventions were ineffective at subduing the pathological remodeling and sustaining cardiac function during CCS. However, their combination was potent at preventing LVSD during CCS by attenuating maladaptive myocardial hypertrophy, fibrosis, and inflammatory responses. The treatment intervention attained its potency mainly via Forskolin-ACs/cAMP-mediated modulation of cardiac and inflammatory responses, coupled with Amlexanox inhibition of GRK5 mediated maladaptive cascades. Taken together, our findings highlight the Amlexanox and Forskolin combination as a potential therapeutic intervention for preventing the occurrence of pathological cardiac hypertrophy during chronic stress.

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Vaspin Alleviates Pathological Cardiac Hypertrophy By Regulating Autophagy-Dependent Myocardial Senescence

10.21203/rs.3.rs-107249/v1 ◽

2020 ◽

Author(s):

Haiying Rui ◽

Ruochuan Li ◽

Lulu Liu ◽

Ziqi Han ◽

Huaxiang Yu ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Kinase Inhibitors ◽

Subcutaneous Administration ◽

Autophagic Flux ◽

Protective Effects ◽

Myocardial Cells ◽

Ischaemia Reperfusion Injury ◽

Pathological Cardiac Hypertrophy ◽

First Time

Abstract Background: Visceral adipose tissue derived serine protease inhibitor (vaspin), a secretory adipokine, was reported to play a protective role in insulin resistance. Recent studies have demonstrated that serum vaspin levels are downregulated in patients with coronary artery disease (CAD) and that vaspin has a protective effect on myocardial ischaemia/reperfusion injury (IRI) and atherosclerosis. However, whether vaspin exerts specific effects on pathological cardiac hypertrophy remains unknown.Methods: Pathologic cardiac hypertrophy was induced in male C57BL/6J wild type (WT) and vaspin knockout (vaspin ko) mice. Buparlisib (PI3K inhibitor, 50 mg/kg), rapamycin (mTOR inhibitor, 20 mg/kg), or A 769662 (AMPK agonist, 30 mg/kg) wer e pre and co administered to vaspin ko mice daily for a period of 15 days. Induction of pathological cardiac hypertrophy was performed by the subcutaneous administration of isoproterenol (ISO) (5 mg/kg) into mice from the 7th to the 15th day. Cardiac hype rtrophy, fibrosis, and cardiac function were examined in these mice. Critical characteristics of senescence (senescence associated β galactosidase activity and expression of cyclin dependent kinase inhibitors) were examined in the cardiac hypertrophy modelResults: We provide the first evidence that the serum level of vaspin decreased during pathological cardiac hypertrophy; further, knocking out of vaspin resulted in markedly exaggerated cardiac h ypertrophy and fibrosis, and increased cardiomyocyte senesc senescence in mice treated with ISO. Conversely, the administration of exogenous ence in mice treated with ISO. Conversely, the administration of exogenous recombinant human vaspin in vitro protected myocardial cells against hypertrophy recombinant human vaspin in vitro protected myocardial cells against hypertrophy and senescence caused by ISO. and senescence caused by ISO. MechanisticallyMechanistically, PI3K, PI3K--AKTAKT--mTOR mTOR pathwaypathway--dependent activation of autophadependent activation of autophagic flux was involved in the protective gic flux was involved in the protective effects of vaspin toward cardiac hypertrophy.effects of vaspin toward cardiac hypertrophy.Conclusion: Our results showed for the first time that vaspin functions as a critical Our results showed for the first time that vaspin functions as a critical regulator that alleviates pathological cardiac hypertrophy by regulating regulator that alleviates pathological cardiac hypertrophy by regulating autophagyautophagy--ddependent myocardial senescence, which provides potential preventive and ependent myocardial senescence, which provides potential preventive and therapeutic targets for pathological cardiac hypertrophy.therapeutic targets for pathological cardiac hypertrophy.

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

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/9815039 ◽

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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