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

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

Nutrition & Metabolism ◽

10.1186/s12986-021-00596-7 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Haiyu Li ◽

Xiaoxu Tian ◽

Yongjuan Ruan ◽

Junhui Xing ◽

Zhe Meng

Keyword(s):

Cardiac Hypertrophy ◽

Signaling Pathway ◽

Cardiac Fibroblasts ◽

Akt Signaling ◽

Pathological Process ◽

Heart Weight ◽

Asiatic Acid ◽

Akt Signaling Pathway ◽

Sprague Dawley

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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In vivo cooperation between Bcl‐x L and the phosphoinositide 3‐kinase‐Akt signaling pathway for the protection of epidermal keratinocytes from apoptosis

The FASEB Journal ◽

10.1096/fj.02-0597com ◽

2003 ◽

Vol 17 (6) ◽

pp. 610-620 ◽

Cited By ~ 37

Author(s):

Jiro Umeda ◽

Shigetoshi Sano ◽

Kazuhiko Kogawa ◽

Noboru Motoyama ◽

Kunihiko Yoshikawa ◽

...

Keyword(s):

Signaling Pathway ◽

Akt Signaling ◽

Epidermal Keratinocytes ◽

Akt Signaling Pathway ◽

Phosphoinositide 3 Kinase

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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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Role of phosphoinositide 3-kinase–Akt signaling pathway in the age-related cytokine dysregulation in splenic macrophages stimulated via TLR-2 or TLR-4 receptors

Mechanisms of Ageing and Development ◽

10.1016/j.mad.2011.05.003 ◽

2011 ◽

Vol 132 (6-7) ◽

pp. 274-286 ◽

Cited By ~ 28

Author(s):

Mosoka P. Fallah ◽

R. Lakshman Chelvarajan ◽

Beth A. Garvy ◽

Subbarao Bondada

Keyword(s):

Signaling Pathway ◽

Akt Signaling ◽

Akt Signaling Pathway ◽

Splenic Macrophages ◽

Age Related ◽

Cytokine Dysregulation ◽

Phosphoinositide 3 Kinase

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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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Epigallocatechin-3-gallate (EGCG) reduces apoptosis of preantral follicles through the phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) signaling pathway after in vitro culture of sheep ovarian tissue

Theriogenology ◽

10.1016/j.theriogenology.2020.05.037 ◽

2020 ◽

Vol 155 ◽

pp. 25-32

Author(s):

R.S. Barberino ◽

J.M.S. Santos ◽

T.L.B.G. Lins ◽

V.G. Menezes ◽

A.P.O. Monte ◽

...

Keyword(s):

Protein Kinase ◽

In Vitro Culture ◽

Signaling Pathway ◽

Protein Kinase B ◽

Ovarian Tissue ◽

Akt Signaling ◽

Akt Signaling Pathway ◽

Phosphatidylinositol 3 Kinase ◽

Preantral Follicles

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Downregulation of cAMP-Dependent Protein Kinase Inhibitor-b Promotes Preeclampsia by Decreasing Phosphorylated Akt

Reproductive Sciences ◽

10.1007/s43032-020-00258-8 ◽

2020 ◽

Vol 28 (1) ◽

pp. 178-185

Author(s):

Chunfeng Liu ◽

Hao Wang ◽

Mo Yang ◽

Yiheng Liang ◽

Li Jiang ◽

...

Keyword(s):

Protein Kinase ◽

Matrix Metalloproteinase ◽

Signaling Pathway ◽

Kinase Inhibitor ◽

Akt Signaling ◽

Migration And Invasion ◽

Akt Signaling Pathway ◽

Dependent Protein Kinase ◽

Phosphorylated Akt ◽

Dependent Protein

AbstractPreeclampsia is a multi-system disease that is unique to human pregnancy. Impaired extravillous trophoblast migration and invasion accompanied by poor spiral vascular remodeling is thought to be the initial reason. This study investigated cAMP-dependent protein kinase inhibitor-b(PKIB) expression in placentas and its involvement in the pathogenesis of PE. We used immunohistochemistry and western blotting to calculate PKIB levels in the placentas. Then we knocked down PKIB by siRNA and used real-time cell analysis to assess the invasion and migration ability of trophoblasts. Tube formation assay and spheroid sprouting assay were utilized to identify the ability to form vessels of trophoblasts. At last, western blotting was used to demonstrate the level of phosphorylated Akt, as well as downstream-related genes of Akt signaling pathway in trophoblasts. We first found that PKIB expression level was lower in the PE placentas than in the normal placentas. In addition, we found that downregulation of PKIB can inhibit the migration, invasion, and the ability to form vessels of HTR8/SVneo cells. Downregulation of PKIB leaded to a decrease in phosphorylated Akt, as well as downstream proteins such as matrix metalloproteinase 2, matrix metalloproteinase 9, and glycogen synthase kinase 3β, which are related to migration and invasion. Our study revealed that the downregulation of PKIB expression resulted in decreased migration, invasion, and vessel formation ability by regulating Akt signaling pathway in placental trophoblasts in PE.

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