Asiatic acid alleviates Ang-II induced cardiac hypertrophy and fibrosis via miR-126/PIK3R2 signaling

Abstract Background Cardiac hypertrophy is an independent risk factor of many cardiovascular diseases. Studies have demonstrated that microRNA-126 (miR-126) was involved in angiogenesis during physiological and pathological process. However, its role in cardiac hypertrophy has not been known clearly. Our previous study demonstrated that asiatic acid (AA) has obvious protective effect on cardiac hypertrophy. Here, this study aimed to discover the regulatory role of miR-126 and its mechanism in cardiac hypertrophy, and to determine whether AA’s anti-hypertrophy effect is partially miR-126 dependent. Methods Male Sprague Dawley rats were AngII infused via osmotic minipumps for 4 weeks and were treated with AA (20 mg/kg/day) by oral gavage. Cardiac hypertrophy was assessed using the echocardiography and histological analysis. In vitro studies,cardiomyocyte and cardiac fibroblasts (CF) were treted with AngII and AngII plus AA. And, the effect of AA on miR-126 and PI3K/AKT signaling pathway was investigated. Results Treatment of rats with AA decreased the ratio of heart weight to tibia length and hypertrophy markers. In vitro exprements demonstrated that AA significantly attenuated AngII-induced cardiac growth and cardiac fibroblast collagen expression. Moreover, our results found downregulation of miR-126 and activation of PI3K/AKT signaling pathway in AngII infusion induced cardiac hypertrophy model. It was also determined that miR-126 targets PIK3R2 directly. Conclusions AA supplementation upregulated the expression of miR-126 and conferred cardio-protection effect against AngII induced cardiac hypertrophy.

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Asiatic Acid Alleviates Ang-II Induced Cardiac Hypertrophy and Fibrosis via miR-126/PIK3R2 signaling

10.21203/rs.3.rs-269028/v1 ◽

2021 ◽

Author(s):

Haiyu Li ◽

Xiaoxu Tian ◽

Yongjuan Ruan ◽

Junhui Xing ◽

Zhe Meng

Keyword(s):

Cardiac Hypertrophy ◽

Akt Signaling ◽

Pathological Process ◽

Heart Weight ◽

Asiatic Acid ◽

Akt Signaling Pathway ◽

Sprague Dawley ◽

Cardio Protection ◽

Tibia Length

Abstract BackgroundCardiac hypertrophy is an independent risk factor of many cardiovascular diseases. Studies demonstrated that microRNA-126 (miR-126) was involved in angiogenesis during physiological and pathological process. However, its role in cardiac hypertrophy has not been known clearly. Recent studies demonstrated asiatic acid (AA) has obvious protective effect on cardiac hypertrophy. Here, this study aimed to discover the regulatory role of miR-126 and its mechanism in cardiac hypertrophy, and to determine whether AA’s anti-hypertrophy effect is partially miR-126 dependent. MethodsMale Sprague Dawley (SD) rats were AngII infused via osmotic minipumps for 4 weeks and were treated with AA (20mg/kg/day) by oral gavage. Cardiac protective hypertrophy was assessed using the echocardiography and histological analysis. And, the effect of AA on miR-126 and PI3K/AKT signaling pathway was investigated.ResultsTreatment of rats with AA decreased the ratio of heart weight to tibia length and hypertrophy markers. Moreover, our results found downregulation of miR-126 and activation of PI3K/AKT signaling AngII infusion induced cardiac hypertrophy model. It was also determined that miR-126 targets PIK3R2 directly. ConclusionsAA supplementation upregulated the expression of miR-126 and conferred cardio-protection against AngII induced cardiac hypertrophy.

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Capn4 aggravates angiotensin II-induced cardiac hypertrophy by activating the IGF-AKT signaling pathway

The Journal of Biochemistry ◽

10.1093/jb/mvab100 ◽

2021 ◽

Author(s):

Yuanping Cao ◽

Qun Wang ◽

Caiyun Liu ◽

Wenjun Wang ◽

Songqing Lai ◽

...

Keyword(s):

Angiotensin Ii ◽

Cardiac Hypertrophy ◽

Signaling Pathway ◽

Expression Patterns ◽

Akt Signaling ◽

Calpain Inhibitor ◽

Ang Ii ◽

Akt Signaling Pathway ◽

Calpain Activity

Abstract Capn4 belongs to a family of calpains that participate in a wide variety of biological functions, but little is known about the role of Capn4 in cardiac disease. Here, we show that the expression of Capn4 was significantly increased in Angiotensin II (Ang II)-treated cardiomyocytes and Ang II-induced cardiac hypertrophic mouse hearts. Importantly, in agreement with the Capn4 expression patterns, the maximal calpain activity measured in heart homogenates was elevated in Ang II-treated mice, and oral coadministration of SNJ-1945 (calpain inhibitor) attenuated the total calpain activity measured in vitro. Functional assays indicated that overexpression of Capn4 obviously aggravated Ang II-induced cardiac hypertrophy, whereas Capn4 knockdown resulted in the opposite phenotypes. Further investigation demonstrated that Capn4 maintained the activation of the insulin-like growth factor (IGF)-AKT signaling pathway in cardiomyocytes by increasing c-Jun expression. Mechanistic investigations revealed that Capn4 directly bound and stabilized c-Jun, and knockdown of Capn4 increased the ubiquitination level of c-Jun in cardiomyocytes. Additionally, our results demonstrated that the antihypertrophic effect of Capn4 silencing was partially dependent on the inhibition of c-Jun. Overall, these data suggested that Capn4 contributes to cardiac hypertrophy by enhancing the c-Jun-mediated IGF-AKT signaling pathway and could be a potential therapeutic target for hypertrophic cardiomyopathy.

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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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Naringenin Protects Rats against Ang-II Induced Cardiac Hypertrophy and Fibrosis by Downregulating TGF-β1/Smads Signaling Pathways

10.21203/rs.3.rs-694850/v1 ◽

2021 ◽

Author(s):

Xiaowei Chen ◽

Xi Zhao ◽

Han Wang ◽

Hengdao Liu

Keyword(s):

Signaling Pathway ◽

Cardiac Remodeling ◽

Cardiac Fibroblasts ◽

Biological Properties ◽

Heart Weight ◽

Cardiomyocyte Hypertrophy ◽

In Vitro Experiments ◽

Sprague Dawley ◽

Tgf Β1

Abstract Background:Naringenin (Nrg), a flavone found in several plant foods with various biological properties, has been shown prevention of cardiac remodeling. However, themechanisms underlying this suppression of cardiac remodeling has not been known clearly.Methods: Male Sprague Dawley (SD) rats were AngII infused via osmotic minipumps for 4 weeks and were given Nrg by gavage (100mg/kg/day) at the same time. In vitro experiments used cardiomyocyte and cardiac fibroblasts(CF) treated with AngII or AngII plus Nrg.Cardiac remodeling was assessed using the echocardiography and histological analysis. And, the effect of Nrg on TGF-β1/Smadssignaling pathway was investigated.Results: Treatmentwith Nrg(100mg/kg/day) decreased the ratio of heart weight to tibia length and hypertrophy markers in rats given AngII infusion. In vitro experiments demonstrated that AngII-induced cardiomyocyte hypertrophy and proliferation of CFs were significantly inhibited by Nrg administration. Nrg inhibited activation of the TGF-β1/Smad2/3 signaling pathway stimulated by AngII. Conclusions: Nrgsupplementation prevented cardiac remodeling via down-regulating the TGF-β1/Smad2/3 signaling pathway both in cardiomyocyte and CFs, and attenuating cardiac remodeling in AngII-induced rats model.

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Asiatic Acid Protects against Doxorubicin-Induced Cardiotoxicity in Mice

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/5347204 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12

Author(s):

Xiaoping Hu ◽

Baijun Li ◽

Luocheng Li ◽

Bowen Li ◽

Jinlong Luo ◽

...

Keyword(s):

Cardiac Function ◽

Signaling Pathway ◽

Cardiac Injury ◽

Akt Signaling ◽

Cardiac Complications ◽

Asiatic Acid ◽

Protective Effects ◽

Akt Signaling Pathway ◽

Myocardial Oxidative Stress

The use of doxorubicin (DOX) can result in depression of cardiac function and refractory cardiomyopathy. Currently, there are no effective approaches to prevent DOX-related cardiac complications. Asiatic acid (AA) has been reported to provide cardioprotection against several cardiovascular diseases. However, whether AA could attenuate DOX-related cardiac injury remains unclear. DOX (15 mg/kg) was injected intraperitoneally into the mice to mimic acute cardiac injury, and the mice were given AA (10 mg/kg or 30 mg/kg) for 2 weeks for protection. The data in our study found that AA-treated mice exhibited attenuated cardiac injury and improved cardiac function in response to DOX injection. AA also suppressed myocardial oxidative damage and apoptosis without affecting cardiac inflammation in DOX-treated mice. AA also provided protection in DOX-challenged cardiomyocytes, improved cell viability, and suppressed intracellular reactive oxygen species (ROS) in vitro. Detection of signaling pathways showed that AA activated protein kinase B (AKT) signaling pathway in vivo and in vitro. Furthermore, we found that AA lost its protective effects in the heart with AKT inactivation. In conclusion, our results found that AA could attenuate DOX-induced myocardial oxidative stress and apoptosis via activation of the AKT signaling pathway.

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Phosphoinositide 3-kinase Akt signaling pathway interacts with protein kinase Cβ2 in the regulation of physiologic developmental hypertrophy and heart function

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00562.2008 ◽

2009 ◽

Vol 296 (3) ◽

pp. H566-H572 ◽

Cited By ~ 19

Author(s):

Debra L. Rigor ◽

Natalya Bodyak ◽

Soochan Bae ◽

Jun H. Choi ◽

Li Zhang ◽

...

Keyword(s):

Protein Kinase ◽

Transgenic Mice ◽

Cardiac Hypertrophy ◽

Signaling Pathway ◽

Akt Signaling ◽

Potential Interaction ◽

Pi3 Kinase ◽

Heart Weight ◽

Akt Signaling Pathway ◽

Phosphoinositide 3 Kinase

The phosphoinositide 3-kinase (PI3-kinase)-protein kinase B (Akt) signaling pathway is essential in the induction of physiological cardiac hypertrophy. In contrast, protein kinase C β2 (PKCβ2) is implicated in the development of pathological cardiac hypertrophy and heart failure. Thus far, no clear association has been demonstrated between these two pathways. In this study, we examined the potential interaction between the PI3-kinase and PKCβ2 pathways by crossing transgenic mice with cardiac specific expression of PKCβ2, constitutively active (ca) PI3-kinase, and dominant-negative (dn) PI3-kinase. In caPI3-kinase/PKCβ2 and dnPI3-kinase/PKCβ2 double-transgenic mice, the heart weight-to-body weight ratios and cardiomyocyte sizes were similar to those observed in caPI3-kinase and dnPI3-kinase transgenic mice, respectively, suggesting that the regulation of physiological developmental hypertrophy via modulation of cardiomyocyte size proceeds through the PI3-kinase pathway. In addition, we observed that caPI3-kinase/PKCβ2 mice showed improved cardiac function while the function of dnPI3-kinase/PKCβ2 mice was similar to that of the PKCβ2 group. PKCβ2 protein levels in both dnPI3-kinase/PKCβ2 and PKCβ2 mice were significantly upregulated. Interestingly, however, PKCβ2 protein expression was significantly attenuated in caPI3-kinase/PKCβ2 mice. PI3-kinase activity measured by Akt phosphorylation was not affected by PKCβ2 overexpression. These data suggest a potential interaction between these two pathways in the heart, where PI3-kinase is predominantly responsible for the regulation of physiological developmental hypertrophy and may act as an upstream modulator of PKCβ2 with the potential for rescuing the pathological cardiac dysfunction induced by overexpression of PKCβ.

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Nobiletin enhances the development and quality of bovine embryos in vitro during two key periods of embryonic genome activation

Scientific Reports ◽

10.1038/s41598-021-91158-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Karina Cañón-Beltrán ◽

Yulia N. Cajas ◽

Serafín Peréz-Cerezales ◽

Claudia L. V. Leal ◽

Ekaitz Agirregoitia ◽

...

Keyword(s):

Embryonic Development ◽

Signaling Pathway ◽

Akt Signaling ◽

Mitochondrial Activity ◽

Bovine Embryos ◽

Akt Signaling Pathway ◽

Cell Stage ◽

Development In Vitro

AbstractIn vitro culture can alter the development and quality of bovine embryos. Therefore, we aimed to evaluate whether nobiletin supplementation during EGA improves embryonic development and blastocyst quality and if it affects PI3K/AKT signaling pathway. In vitro zygotes were cultured in SOF + 5% FCS (Control) or supplemented with 5, 10 or 25 µM nobiletin (Nob5, Nob10, Nob25) or with 0.03% dimethyl-sulfoxide (CDMSO) during minor (2 to 8-cell stage; MNEGA) or major (8 to 16-cell stage; MJEGA) EGA phase. Blastocyst yield on Day 8 was higher in Nob5 (42.7 ± 1.0%) and Nob10 (44.4 ± 1.3%) for MNEGA phase and in Nob10 (61.0 ± 0.8%) for MJEGA phase compared to other groups. Mitochondrial activity was higher and lipid content was reduced in blastocysts produced with nobiletin, irrespective of EGA phase. The mRNA abundance of CDK2, H3-3B, H3-3A, GPX1, NFE2L2 and PPARα transcripts was increased in 8-cells, 16-cells and blastocysts from nobiletin groups. Immunofluorescence analysis revealed immunoreactive proteins for p-AKT forms (Thr308 and Ser473) in bovine blastocysts produced with nobiletin. In conclusion, nobiletin supplementation during EGA has a positive effect on preimplantation bovine embryonic development in vitro and corroborates on the quality improvement of the produced blastocysts which could be modulated by the activation of AKT signaling pathway.

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