Baicalin Attenuates Cardiac Dysfunction and Myocardial Remodeling in a Chronic Pressure-Overload Mice Model

Background/Aims: Baicalin has been shown to be effective for various animal models of cardiovascular diseases, such as pulmonary hypertension, atherosclerosis and myocardial ischaemic injury. However, whether baicalin plays a role in cardiac hypertrophy remains unknown. Here we investigated the protective effects of baicalin on cardiac hypertrophy induced by pressure overload and explored the potential mechanisms involved. Methods: C57BL/6J-mice were treated with baicalin or vehicle following transverse aortic constriction or Sham surgery for up to 8 weeks, and at different time points, cardiac function and heart size measurement and histological and biochemical examination were performed. Results: Mice under pressure overload exhibited cardiac dysfunction, high mortality, myocardial hypertrophy, increased apoptosis and fibrosis markers, and suppressed cardiac expression of PPARα and PPARβ/δ. However, oral administration of baicalin improved cardiac dysfunction, decreased mortality, and attenuated histological and biochemical changes described above. These protective effects of baicalin were associated with reduced heart and cardiomyocyte size, lower fetal genes expression, attenuated cardiac fibrosis, lower expression of profibrotic markers, and decreased apoptosis signals in heart tissue. Moreover, we found that baicalin induced PPARα and PPARβ/δ expression in vivo and in vitro. Subsequent experiments demonstrated that long-term baicalin treatment presented no obvious cardiac lipotoxicity. Conclusions: The present results demonstrated that baicalin attenuates pressure overload induced cardiac dysfunction and ventricular remodeling, which would be due to suppressed cardiac hypertrophy, fibrosis, apoptosis and metabolic abnormality.

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A77 1726 (leflunomide) blocks and reverses cardiac hypertrophy and fibrosis in mice

Clinical Science ◽

10.1042/cs20180160 ◽

2018 ◽

Vol 132 (6) ◽

pp. 685-699 ◽

Cited By ~ 20

Author(s):

Zhen-Guo Ma ◽

Xin Zhang ◽

Yu-Pei Yuan ◽

Ya-Ge Jin ◽

Ning Li ◽

...

Keyword(s):

T Cell ◽

Cardiac Hypertrophy ◽

Protective Effect ◽

Signaling Pathway ◽

Cardiac Fibrosis ◽

Pressure Overload ◽

Akt Signaling ◽

Akt Signaling Pathway

T-cell infiltration and the subsequent increased intracardial chronic inflammation play crucial roles in the development of cardiac hypertrophy and heart failure (HF). A77 1726, the active metabolite of leflunomide, has been reported to have powerful anti-inflammatory and T cell-inhibiting properties. However, the effect of A77 1726 on cardiac hypertrophy remains completely unknown. Herein, we found that A77 1726 treatment attenuated pressure overload or angiotensin II (Ang II)-induced cardiac hypertrophy in vivo, as well as agonist-induced hypertrophic response of cardiomyocytes in vitro. In addition, we showed that A77 1726 administration prevented induction of cardiac fibrosis by inhibiting cardiac fibroblast (CF) transformation into myofibroblast. Surprisingly, we found that the protective effect of A77 1726 was not dependent on its T lymphocyte-inhibiting property. A77 1726 suppressed the activation of protein kinase B (AKT) signaling pathway, and overexpression of constitutively active AKT completely abolished A77 1726-mediated cardioprotective effects in vivo and in vitro. Pretreatment with siRNA targetting Fyn (si Fyn) blunted the protective effect elicited by A77 1726 in vitro. More importantly, A77 1726 was capable of blocking pre-established cardiac hypertrophy in mice. In conclusion, A77 1726 attenuated cardiac hypertrophy and cardiac fibrosis via inhibiting FYN/AKT signaling pathway.

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Low‐intensity Pulsed Ultrasound Ameliorates Angiotension Ii-induced Cardiac Fibrosisbyalleviating Inflammation via a Caveolin-1-dependent Pathway

10.21203/rs.3.rs-37027/v1 ◽

2020 ◽

Author(s):

Kun Zhao ◽

Jing Zhang ◽

Tianhua Xu ◽

Chuanxi Yang ◽

Liqing Weng ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Cardiac Fibrosis ◽

Ventricular Remodeling ◽

Left Ventricular Remodeling ◽

Left Ventricular ◽

Pulsed Ultrasound ◽

Caveolin 1 ◽

Low Intensity Pulsed Ultrasound

Abstract Background: Cardiac hypertrophy and fibrosis are major pathological manifestations observed in left ventricular remodeling induced by Angiotensin II (AngII). Concerning the fact that low‐intensity pulsed ultrasound (LIPUS) has been reported to improve cardiac dysfunction and myocardial fibrosis in myocardial infarction (MI) through mechanotransductionanditsdownstream pathways, we aimed to investigate whether LIPUS could also exert a protective effect on ameliorating AngII-induced cardiac hypertrophy and fibrosis andand if so, to further elucidate the underlying molecular mechanisms.Methods: In our study, we used AngII to mimic the animal and cell culture models of cardiac hypertrophy and fibrosis, where LIPUS irradiation (0.5MHz, 77.20mW/cm2) was applied for 20 minutes every 2 days from 1 week before surgery to 4 weeks after surgery in vivo, and every 6 hours for a total of 2 times in vitro. Following that, the levels of cardiac hypertrophy and fibrosis were evaluated by echocardiographic, histopathological, and molecular biological methods. Results: Our results showed that LIPUS irradiation could ameliorate left ventricular remodeling in vivo and cardiac fibrosis in vitro by reducing AngII-inducedrelease of inflammatory cytokines, while the protective effects were limited on cardiac hypertrophy in vitro. Given that LIPUS irradiation increased the expression of caveolin-1 related to mechanical stimulation, we inhibited caveolin-1 activity with pyrazolopyrimidine 2 (pp2) in vitro, by which LIPUS-induced downregulation of inflammation was reversed and the anti-fibrosis effects of LIPUS irradiation were absent. Conclusions: Taken together, these results indicate that LIPUS irradiation could ameliorate AngII-induced cardiac fibrosis by alleviating inflammation via a caveolin-1-dependent pathway, providing new insights for the development of novel therapeuticapparatus in clinical practice.

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MiR-22 Inhibition Alleviates Cardiac Dysfunction in Doxorubicin-Induced Cardiomyopathy by Targeting the sirt1/PGC-1α Pathway

Frontiers in Physiology ◽

10.3389/fphys.2021.646903 ◽

2021 ◽

Vol 12 ◽

Author(s):

Runze Wang ◽

Yuerong Xu ◽

Xiaolin Niu ◽

Yexian Fang ◽

Dong Guo ◽

...

Keyword(s):

Cardiac Dysfunction ◽

Poor Prognosis ◽

Cardiac Fibrosis ◽

Underlying Mechanism ◽

Protective Effects ◽

Loss Of Function ◽

Life Threatening

Doxorubicin (DOX) cardiotoxicity is a life-threatening side effect that leads to a poor prognosis in patients receiving chemotherapy. We investigated the role of miR-22 in doxorubicin-induced cardiomyopathy and the underlying mechanism in vivo and in vitro. Specifically, we designed loss-of-function and gain-of-function experiments to identify the role of miR-22 in doxorubicin-induced cardiomyopathy. Our data suggested that inhibiting miR-22 alleviated cardiac fibrosis and cardiac dysfunction induced by doxorubicin. In addition, inhibiting miR-22 mitigated mitochondrial dysfunction through the sirt1/PGC-1α pathway. Knocking out miR-22 enhanced mitochondrial biogenesis, as evidenced by increased PGC-1α, TFAM, and NRF-1 expression in vivo. Furthermore, knocking out miR-22 rescued mitophagy, which was confirmed by increased expression of PINK1 and parkin and by the colocalization of LC3 and mitochondria. These protective effects were abolished by overexpressing miR-22. In conclusion, miR-22 may represent a new target to alleviate cardiac dysfunction in doxorubicin-induced cardiomyopathy and improve prognosis in patients receiving chemotherapy.

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Kaempferol Alleviates Angiotensin II-Induced Cardiac Dysfunction and Interstitial Fibrosis in Mice

Cellular Physiology and Biochemistry ◽

10.1159/000484304 ◽

2017 ◽

Vol 43 (6) ◽

pp. 2253-2263 ◽

Cited By ~ 14

Author(s):

Yuan Liu ◽

Lu Gao ◽

Sen Guo ◽

Yuzhou Liu ◽

Xiaoyan Zhao ◽

...

Keyword(s):

Angiotensin Ii ◽

Cardiac Hypertrophy ◽

Cardiac Dysfunction ◽

Cardiac Fibrosis ◽

Neonatal Rat ◽

Cardiac Remodelling ◽

Ang Ii ◽

Ventricular Fibrosis

Background/Aims: Endothelial-to-mesenchymal transition (EndMT) is a mechanism that promotes cardiac fibrosis induced by Angiotensin II (AngII). Kaempferol (KAE) is a monomer component mainly derived from the rhizome of Kaempferia galanga L. It shows anti-inflammatory, anti-oxidative, anti-microbial and anti-cancer properties, which can be used in the treatment of cancer, cardiovascular diseases, infection, etc. But, its effects on the development of cardiac remodelling remain completely unknown. The aim of the present study was to determine whether KAE attenuates cardiac hypertrophy induced by angiotensin II (Ang II) in cultured neonatal rat cardiac myocytes in vitro and cardiac hypertrophy induced by AngII infusion in mice in vivo. Methods: Male wild-type mice aged 8-10 weeks with or without KAE were subjected to AngII or saline, to induce fibrosis or as a control, respectively. Morphological changes, echocardiographic parameters, histological analyses, and hypertrophic markers were also used to evaluate hypertrophy. Results: KAE prevented and reversed cardiac remodelling induced by AngII. The KAE in this model exerted no basal effects but attenuated cardiac fibrosis, hypertrophy and dysfunction induced by AngII. Both in vivo and in vitro experiments demonstrated that Ang II infusion or TGF-β induced EndMT can be reduced by KAE and the proliferation and activation of cardiac fibroblasts (CFs) can be inhibited by KAE. Conclusions: The results suggest that KAE prevents and reverses ventricular fibrosis and cardiac dysfunction, providing an experimental basis for clinical treatment on ventricular fibrosis.

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Probiotic and Functional Properties of Limosilactobacillus reuteri INIA P572

Nutrients ◽

10.3390/nu13061860 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1860

Author(s):

Patricia Diez-Echave ◽

Izaskun Martín-Cabrejas ◽

José Garrido-Mesa ◽

Susana Langa ◽

Teresa Vezza ◽

...

Keyword(s):

In Vitro Assays ◽

Immunomodulatory Activity ◽

Probiotic Properties ◽

Protective Effects ◽

Mice Model ◽

In Vivo Models ◽

Food Borne ◽

Gastrointestinal Conditions

Limosilactobacillus reuteri INIA P572 is a strain able to produce the antimicrobial compound reuterin in dairy products, exhibiting a protective effect against some food-borne pathogens. In this study, we investigated some probiotic properties of this strain such as resistance to gastrointestinal passage or to colonic conditions, reuterin production in a colonic environment, and immunomodulatory activity, using different in vitro and in vivo models. The results showed a high resistance of this strain to gastrointestinal conditions, as well as capacity to grow and produce reuterin in a human colonic model. Although the in vitro assays using the RAW 264.7 macrophage cell line did not demonstrate direct immunomodulatory properties, the in vivo assays using a Dextran Sulphate Sodium (DSS)-induced colitic mice model showed clear immunomodulatory and protective effects of this strain.

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Abstract 277: Microrna-33 Promotes Cardiac Fibrosis by Maintaining Cellular Lipid Homeostasis

Circulation Research ◽

10.1161/res.119.suppl_1.277 ◽

2016 ◽

Vol 119 (suppl_1) ◽

Author(s):

Masataka Nishiga ◽

Takahiro Horie ◽

Yasuhide Kuwabara ◽

Osamu Baba ◽

Tetsushi Nakao ◽

...

Keyword(s):

Cardiac Fibrosis ◽

Cardiac Fibroblasts ◽

Pressure Overload ◽

Cholesterol Content ◽

Atp Binding Cassette Transporter ◽

Primary Fibroblasts ◽

Proliferation In Vitro ◽

Altered Lipid

Background: A highly conserved microRNA, miR-33 is considered as a potential therapeutic target for atherosclerosis, because recent reports, including ours, indicated miR-33 has atherogenic effects by reducing HDL-C. However, the functions of miR-33 in heart failure remain to be elucidated. Methods and results: To clarify the functions of miR-33 involved in cardiac hypertrophy and fibrosis in vivo, we investigated the responses to pressure overload by transverse aortic constriction (TAC) in miR-33 deficient (KO) mice. When subjected to TAC, miR-33 expression level was significantly up-regulated in wild-type (WT) left ventricles, whereas miR-33 KO hearts displayed no less hypertrophic responses than WT hearts. However, interestingly, histological and gene expression analyses showed ameliorated cardiac fibrosis in miR-33 KO hearts compared to WT hearts. Furthermore, we generated cardiac fibroblast specific miR-33 deficient mice, which also showed ameliorated cardiac fibrosis when they were subjected to TAC. We also found that cardiac fibroblasts were mainly responsible for miR-33 expression in the heart, because its expression was about 4-folds higher in isolated primary cardiac fibroblasts than cardiomyocytes. Deficiency of miR-33 impaired cell proliferation in primary fibroblasts, which was considered due to altered lipid raft cholesterol content by up-regulated ATP-binding cassette transporter A1/G1. Conclusion: Deficiency of miR-33 impaired fibroblast proliferation in vitro, and ameliorated cardiac fibrosis induced by pressure overload in vivo.

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Abstract 292: TRPA1 Promoting Myofibroblast Differentiation Mediate Pressure Overload-Induced Cardiac Fibrosis

Circulation ◽

10.1161/circ.138.suppl_2.292 ◽

2018 ◽

Vol 138 (Suppl_2) ◽

Author(s):

Shuang Li ◽

Dong Han ◽

Dachun Yang

Keyword(s):

Knockout Mice ◽

Molecular Mechanisms ◽

Cardiac Fibrosis ◽

Transient Receptor Potential ◽

Transforming Growth Factor ◽

Ventricular Remodeling ◽

Cardiac Fibroblasts ◽

Gene Transfection ◽

Pressure Overload

Background: Hypertensive ventricular remodeling is a common cause of heart failure. Activation and accumulation of cardiac fibroblasts is the key contributors to this progression. Our previous studies indicate that transient receptor potential ankyrin 1 (TRPA1), a Ca 2+ channel necessary and sufficient, play a prominent role in ventricular remodeling. However, the molecular mechanisms regulating remain poorly understood. Methods: We used TRPA1 agonists cinnamaldehyde (CA) pretreatment and TRPA1 knockout mice to understand the role of TRPA1 in ventricular remodeling of hypertensive heart. We also examine the mechanisms through gene transfection and in vitro experiments. Results: TRPA1 overexpression fully activated myofibroblast transformation, while fibroblasts lacking TRPA1 were refractory to transforming growth factor β (TGF-β) -induced transdifferentiation. TRPA1 knockout mice showed hypertensive ventricular remodeling reversal following pressure overload. We found that the TGF-β induced TRPA1 expression through calcineurin-NFAT-Dyrk1A signaling pathway via the TRPA1 promoter. Once induced, TRPA1 activates the Ca 2+ -responsive protein phosphatase calcineurin, which itself induced myofibroblast transdifferentiation. Moreover, inhibition of calcineurin prevented TRPA1-dependent transdifferentiation. Conclusion: Our study provides the first evidence that TRPA1 regulation in cardiac fibroblasts transformation in response to hypertensive stimulation. The results suggesting a comprehensive pathway for myofibroblast formation in conjunction with TGF-β, Calcineurin, NFAT and Dyrk1A. Furthermore, these data indicate that negative modulation of cardiac fibroblast TRPA1 may represent a therapeutic strategy against hypertensive cardiac remodeling.

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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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Novel role for cardiac myocyte-derived β-2 microglobulin in mediating cardiac fibrosis

Clinical Science ◽

10.1042/cs20180681 ◽

2018 ◽

Vol 132 (19) ◽

pp. 2117-2120

Author(s):

Michael J. Boyer ◽

Satoru Eguchi

Keyword(s):

Cardiac Fibrosis ◽

Cardiac Myocyte ◽

Cardiac Fibroblasts ◽

Significant Risk ◽

Growth Factor Receptor ◽

Pressure Overload ◽

Significant Risk Factor ◽

Cardiac Complications

Hypertension is a significant risk factor for the development of cardiovascular ailments, including ischemic heart disease and diastolic dysfunction. In a recent issue of Clinical Science, Li et al. [Clin. Sci. (2018) 132, 1855–1874] report that β-2 microglobulin (β2M) is a novel secreted soluble factor released by cardiac myocytes during pressure overload that promotes profibrotic gene expression in cardiac fibroblasts both in vitro and in vivo. Their study further identifies elevated β2M levels as a possible biomarker for hypertensive patients with cardiac complications. The authors propose a mechanism that mechanically stretched cardiomyocytes release soluble β2M which, through paracrine communication with cardiac fibroblasts, transactivates epidermal growth factor receptor (EGFR) to initiate acute signal transduction and up-regulate profibrotic genes, thereby promoting fibrosis. Here, we will discuss the background, significance of the study, alternative mechanisms, and future directions.

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