Pentoxifylline Ameliorates Cardiac Fibrosis, Pathological Hypertrophy, and Cardiac Dysfunction in Angiotensin II-induced Hypertensive Rats

Sterol Regulatory Element Binding Protein (SREBP)-1 is a transcription factor for triglyceride synthesis. SREBP-1 is shown to contribute to the organ damages such as pancreatic beta cell, liver, and kidney; however, it is unclear whether SREBP-1 also contributes to the cardiac pathogenesis. We made cardiac dysfunction and fibrosis model by 2-week infusion of angiotensin II (A-II, 1.44 mg/kg BW/day). Mice were divided into followings (n=5∼6 in each group): wild with vehicle (WC), wild with A-II (WA), SREBP-1 knockout mice (SREBP-KO) with vehicle (SC), and SREBP-KO with A-II (SA). WA clearly demonstrated cardiac dysfunction and severe perivascular fibrosis compared to WC; however, these findings were not observed in SA compared to SC. We analyzed gene expression by DNA microarray using the software DAVID and quantitative RT-PCR to find gene clusters mostly illustrative for these phenotypes. Gene expression of extracellular matrix (Col1a, 3a, periostin) was increased in WA. Highly scored annotations in WA were chemokines (CCL5, CXCL10) and their receptors (CCR5, CXCR3), and Th2 cytokines (IL-13 and TGFb), suggesting that chronic inflammatory and repairing responses occurred. These changes were normalized in SA compared to SC. Expression of NOX4, a component of NADPH oxidase, was significantly increased in WA and SA compared to each control in a similar extent, suggesting that the Ang II-induced oxidative stress to the heart did not differ. To elucidate why the cardiac fibrosis differed between WA and SA, we analyzed the expression of transcription factors. Nrf2, a transcription factor for detoxification and anti-oxidant gene against to reactive oxygen species (ROS), was significantly decreased in WA compared to WC; however, it did not differ between in SA and SC. Furthermore, expression of the Nrf2-inducible genes HO-1 and NQO1, antioxidant genes, was significantly decreased in WA compared to WC; meanwhile, there were no differences between in SA and SC. [Conclusion] SREBP-1 may positively contribute to the A-II-induced cardiac fibrosis via the involvement of chronic inflammatory responses, which is induced partly by the reduction of antioxidant activity.

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Angiotensin II AT 1 Receptor Blockade Reverses Pathological Hypertrophy and Inflammation in Brain Microvessels of Spontaneously Hypertensive Rats

Stroke ◽

10.1161/01.str.0000129788.26346.18 ◽

2004 ◽

Vol 35 (7) ◽

pp. 1726-1731 ◽

Cited By ~ 130

Author(s):

Hiromichi Ando ◽

Jin Zhou ◽

Miroslava Macova ◽

Hans Imboden ◽

Juan M. Saavedra

Keyword(s):

Angiotensin Ii ◽

Spontaneously Hypertensive Rats ◽

Receptor Blockade ◽

Hypertensive Rats ◽

Spontaneously Hypertensive ◽

Brain Microvessels ◽

Pathological Hypertrophy

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Angiotensin II–induced cardiomyocyte hypertrophy and cardiac fibrosis in stroke-prone spontaneously hypertensive rats

Journal of Laboratory and Clinical Medicine ◽

10.1067/mlc.2000.105617 ◽

2000 ◽

Vol 135 (4) ◽

pp. 353-359 ◽

Cited By ~ 21

Author(s):

Yoshio Ikeda ◽

Takamichi Nakamura ◽

Hajime Takano ◽

Hideaki Kimura ◽

Jun-Ei Obata ◽

...

Keyword(s):

Angiotensin Ii ◽

Spontaneously Hypertensive Rats ◽

Cardiac Fibrosis ◽

Cardiomyocyte Hypertrophy ◽

Hypertensive Rats ◽

Spontaneously Hypertensive

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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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(-)-Epicatechin Inhibits Cardiac Fibrosis via SIRT1/AKT/GSK3β Pathway

10.21203/rs.3.rs-484230/v1 ◽

2021 ◽

Author(s):

Yuanyuan Guo ◽

Yingchun Luo ◽

Zeng Wang ◽

zengxiang dong ◽

Yue Li

Keyword(s):

Angiotensin Ii ◽

Mechanism Of Action ◽

Cardiac Dysfunction ◽

Molecular Mechanisms ◽

Cardiac Fibrosis ◽

Cardiac Fibroblasts ◽

Cardioprotective Effect ◽

Protective Effects ◽

Collagen Production ◽

Transaortic Constriction

Abstract Background: (-)-Epicatechin (EPI) is an important substance involved in protective effects of flavanol-rich foods. Many studies indicate EPI has cardioprotective effect, but the effect of EPI in inhibition of cardiac fibrosis is unclear. Thus, we aimed to evaluate the effect of EPI in preventing cardiac fibrosis and unveil the molecular mechanisms. Methods: Cardiac fibrosis model was established by transaortic constriction (TAC). The acutely isolated cardiac fibroblasts were induced to myofibroblasts with angiotensin II (AngII). Results: EPI markedly attenuated TAC-induced cardiac dysfunction and fibrosis in mice. In cultured CFs, EPI blocked AngII-induced myofibroblast transformation and collagen production. Furthermore, EPI conducted anti-fibrotic effects by activating the the SIRT1/AKT/GSK3β pathway. Conclusions: These findings will supply new agent and mechanism of action for treating cardiac fibrosis in the future.

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Celastrol Attenuates Angiotensin II–Induced Cardiac Remodeling by Targeting STAT3

Circulation Research ◽

10.1161/circresaha.119.315861 ◽

2020 ◽

Vol 126 (8) ◽

pp. 1007-1023 ◽

Cited By ~ 9

Author(s):

Shiju Ye ◽

Wu Luo ◽

Zia A. Khan ◽

Gaojun Wu ◽

Lina Xuan ◽

...

Keyword(s):

Heart Failure ◽

Angiotensin Ii ◽

Cardiac Dysfunction ◽

Cardiac Fibrosis ◽

Nuclear Translocation ◽

Heart Function ◽

Ang Ii ◽

Transverse Aortic Constriction ◽

Aortic Constriction

Rationale: Excessive Ang II (angiotensin II) levels lead to a profibrotic and hypertrophic milieu that produces deleterious remodeling and dysfunction in hypertension-associated heart failure. Agents that disrupt Ang II–induced cardiac dysfunction may have clinical utility in the treatment of hypertension-associated heart failure. Objective: We have examined the potential effect of celastrol—a bioactive compound derived from the Celastraceae family—on Ang II–induced cardiac dysfunction. Methods and Results: In rat primary cardiomyocytes and H9C2 (rat cardiomyocyte-like H9C2) cells, celastrol attenuates Ang II–induced cellular hypertrophy and fibrotic responses. Proteome microarrays, surface plasmon resonance, competitive binding assays, and molecular simulation were used to identify the molecular target of celastrol. Our data showed that celastrol directly binds to and inhibits STAT (signal transducer and activator of transcription)-3 phosphorylation and nuclear translocation. Functional tests demonstrated that the protection of celastrol is afforded through targeting STAT3. Overexpression of STAT3 dampens the effect of celastrol by partially rescuing STAT3 activity. Finally, we investigated the in vivo effect of celastrol treatment in mice challenged with Ang II and in the transverse aortic constriction model. We show that celastrol administration protected heart function in Ang II–challenged and transverse aortic constriction–challenged mice by inhibiting cardiac fibrosis and hypertrophy. Conclusions: Our studies show that celastrol inhibits Ang II–induced cardiac dysfunction by inhibiting STAT3 activity.

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Endothelial Forkhead Box Transcription Factor P1 Regulates Pathological Cardiac Remodeling Through Transforming Growth Factor-β1–Endothelin-1 Signal Pathway

Circulation ◽

10.1161/circulationaha.119.039767 ◽

2019 ◽

Vol 140 (8) ◽

pp. 665-680 ◽

Cited By ~ 10

Author(s):

Jie Liu ◽

Tao Zhuang ◽

Jingjiang Pi ◽

Xiaoli Chen ◽

Qi Zhang ◽

...

Keyword(s):

Angiotensin Ii ◽

Cardiac Remodeling ◽

Cardiac Dysfunction ◽

Cardiac Fibrosis ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β1 ◽

Target Delivery ◽

Endothelin 1 ◽

Forkhead Box ◽

Tgf Β1

Background: Pathological cardiac fibrosis and hypertrophy, the common features of left ventricular remodeling, often progress to heart failure. Forkhead box transcription factor P1 (Foxp1) in endothelial cells (ECs) has been shown to play an important role in heart development. However, the effect of EC-Foxp1 on pathological cardiac remodeling has not been well clarified. This study aims to determine the role of EC-Foxp1 in pathological cardiac remodeling and the underlying mechanisms. Methods: Foxp1 EC-specific loss-of-function and gain-of-function mice were generated, and an angiotensin II infusion or a transverse aortic constriction operation mouse model was used to study the cardiac remodeling mechanisms. Foxp1 downstream target gene transforming growth factor-β1 (TGF-β1) was confirmed by chromatin immunoprecipitation and luciferase assays. Finally, the effects of TGF-β1 blockade on EC-Foxp1 deletion–mediated profibrotic and prohypertrophic phenotypic changes were further confirmed by pharmacological inhibition, more specifically by RGD-peptide magnetic nanoparticle target delivery of TGF-β1–siRNA to ECs. Results: Foxp1 expression is significantly downregulated in cardiac ECs during angiotensin II–induced cardiac remodeling. EC-Foxp1 deletion results in severe cardiac remodeling, including more cardiac fibrosis with myofibroblast formation and extracellular matrix protein production, as well as decompensated cardiac hypertrophy and further exacerbation of cardiac dysfunction on angiotensin II infusion or transverse aortic constriction operation. In contrast, EC-Foxp1 gain of function protects against pathological cardiac remodeling and improves cardiac dysfunction. TGF-β1 signals are identified as Foxp1 direct target genes, and EC-Foxp1 deletion upregulates TGF-β1 signals to promote myofibroblast formation through fibroblast proliferation and transformation, resulting in severe cardiac fibrosis. Moreover, EC-Foxp1 deletion enhances TGF-β1–promoted endothelin-1 expression, which significantly increases cardiomyocyte size and reactivates cardiac fetal genes, leading to pathological cardiac hypertrophy. Correspondingly, these EC-Foxp1 deletion–mediated profibrotic and prohypertrophic phenotypic changes and cardiac dysfunction are normalized by the blockade of TGF-β1 signals through pharmacological inhibition and RGD-peptide magnetic nanoparticle target delivery of TGF-β1–siRNA to ECs. Conclusions: EC-Foxp1 regulates the TGF-β1–endothelin-1 pathway to control pathological cardiac fibrosis and hypertrophy, resulting in cardiac dysfunction. Therefore, targeting the EC–Foxp1–TGF-β1–endothelin-1 pathway might provide a future novel therapy for heart failure.

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