GPR39 promotes cardiac hypertrophy by regulating the AMPK‐mTOR pathway and protein synthesis

2021 ◽  
Author(s):  
Hongjuan Liao ◽  
Weinian Gao ◽  
Jie Ma ◽  
Hongyuan Xue ◽  
Yi Wang ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Cardiac Hypertrophy ◽  
Mtor Pathway

scholarly journals KLK11 promotes the activation of mTOR and protein synthesis to facilitate cardiac hypertrophy

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yi Wang ◽  
Hongjuan Liao ◽  
Yueheng Wang ◽  
Jinlin Zhou ◽  
Feng Wang ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Western Blot ◽  
Real Time ◽  
Real Time Pcr ◽  
Mtor Signaling ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
Quantitative Real Time Pcr

Abstract Background Cardiovascular diseases have become the leading cause of death worldwide, and cardiac hypertrophy is the core mechanism underlying cardiac defect and heart failure. However, the underlying mechanisms of cardiac hypertrophy are not fully understood. Here we investigated the roles of Kallikrein 11 (KLK11) in cardiac hypertrophy. Methods Human and mouse hypertrophic heart tissues were used to determine the expression of KLK11 with quantitative real-time PCR and western blot. Mouse cardiac hypertrophy was induced by transverse aortic constriction (TAC), and cardiomyocyte hypertrophy was induced by angiotensin II. Cardiac function was analyzed by echocardiography. The signaling pathway was analyzed by western blot. Protein synthesis was monitored by the incorporation of [3H]-leucine. Gene expression was analyzed by quantitative real-time PCR. Results The mRNA and protein levels of KLK11 were upregulated in human hypertrophic hearts. We also induced cardiac hypertrophy in mice and observed the upregulation of KLK11 in hypertrophic hearts. Our in vitro experiments demonstrated that KLK11 overexpression promoted whereas KLK11 knockdown repressed cardiomyocytes hypertrophy induced by angiotensin II, as evidenced by cardiomyocyte size and the expression of hypertrophy-related fetal genes. Besides, we knocked down KLK11 expression in mouse hearts with adeno-associated virus 9. Knockdown of KLK11 in mouse hearts inhibited TAC-induced decline in fraction shortening and ejection fraction, reduced the increase in heart weight, cardiomyocyte size, and expression of hypertrophic fetal genes. We also observed that KLK11 promoted protein synthesis, the key feature of cardiomyocyte hypertrophy, by regulating the pivotal machines S6K1 and 4EBP1. Mechanism study demonstrated that KLK11 promoted the activation of AKT-mTOR signaling to promote S6K1 and 4EBP1 pathway and protein synthesis. Repression of mTOR with rapamycin blocked the effects of KLK11 on S6K1 and 4EBP1 as well as protein synthesis. Besides, rapamycin treatment blocked the roles of KLK11 in the regulation of cardiomyocyte hypertrophy. Conclusions Our findings demonstrated that KLK11 promoted cardiomyocyte hypertrophy by activating AKT-mTOR signaling to promote protein synthesis.

Abstract 076: Lapatinib Reduced Cardiac Hypertrophy Induced By Combined Use Of A Pi3k-mtor Dual Inhibitor And Doxorubicin

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Xinhua Yan ◽  
Yongyao Yang ◽  
Juyong Lee ◽  
Jillian Onufrak ◽  
John Fuseler ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Effect ◽  
Mtor Pathway ◽  
Dual Inhibitor ◽  
Cardiac Side Effects ◽  
Compound C ◽  
Transmission Electron ◽  
Combined Use ◽  
Cardioprotective Effects ◽  
Lapatinib Treatment

The HER2-PI3K-mTOR pathway is pivotal for regulating the physiological function of the heart. Currently, drugs targeting the HER2-PI3K-mTOR pathway are either approved or being tested in clinical trials for cancer therapy. It is, therefore, important to evaluate the cardiac effects of using these drugs. In addition, it is necessary to develop countermeasures to prevent the cardiac side effects if any. Methods: Three-month old female FVB/n mice were treated with lapatinib (an HER2 inhibitor) or BEZ235 (BEZ, a PI3K-mTOR dual inhibitor), alone or with doxorubicin (DOX). Cardiac function was monitored by echocardiography and hemodynamic measurements. Cardiac morphology was assessed by confocal microscopy and transmission electron microscopy. The activation of signaling molecules were measured by Western blot analysis. Results: BEZ alone induced cardiac hypertrophy and subsequent heart failure and lapatinib alone induced cardiac failure, in a course of 17 months, respectively. Combination of BEZ with DOX, either concurrently or sequentially, induced cardiac hypertrophy which was associated with higher mortality rate compared to DOX alone. Neuregulin1, a HER receptor ligand worsened, while Lapatinib alleviated, cardiac hypertrophy in these mice. Lapatinib increased the activation of AMPK in DOX+BEZ treated hearts. The cardiac effect of lapatinib was blocked by Compound C, an AMPK inhibitor. Metformin, an AMPK activator, alleviated DOX+BEZ induced cardiac hypertrophy. Conclusions: BEZ or lapatinib treatment alone induced irreversible cardiac dysfunction in mice. Combined use of BEZ and DOX induced cardiac hypertrophy and early mortality, which were prevented by lapatinib. The cardioprotective effects of lapatinib may rely on activating AMPK in the heart.

NLRC5 enhances autophagy via inactivation of AKT/mTOR pathway and ameliorates cardiac hypertrophy

2021 ◽  
Author(s):  
Bayinsilema Ba ◽  
Abudoukelimu Mayila ◽  
Yankai Guo ◽  
Jie Xu ◽  
Shifeng Xing ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Mtor Pathway

Protein metabolism in cardiac hypertrophy and heart failure

1964 ◽  
Vol 206 (2) ◽  
pp. 294-298 ◽  
Author(s):  
Sigmundur Gudbjarnason ◽  
Michael Telerman ◽  
Richard J. Bing
Keyword(s):  
Heart Failure ◽  
Protein Synthesis ◽  
Chronic Heart Failure ◽  
Cardiac Hypertrophy ◽  
Protein Metabolism ◽  
Heart Muscle ◽  
Protein Turnover ◽  
Turnover Rate ◽  
Muscle Protein ◽  
Myocardial Failure

The rate of myocardial protein synthesis was studied in hearts of normal rabbits and in hearts of animals with experimentally produced cardiac hypertrophy and with acute and chronic myocardial failure. Cardiac hypertrophy was accompanied by an increase in protein synthesis; however, there was no increased myocardial protein turnover rate. In acute heart failure the rate of myocardial protein synthesis was diminished as compared to protein synthesis during the development of cardiac hypertrophy. In chronic heart failure the relative incorporation of glycine-2-C14 into heart muscle protein was diminished. The turnover rate of myocardial proteins during cardiac hypertrophy was not altered.

scholarly journals Pathways regulating equine skeletal muscle protein synthesis respond in a dose-dependent manner to graded levels of protein intake

2020 ◽  
Vol 98 (9) ◽  
Author(s):  
Caroline M M Loos ◽  
Kyle R McLeod ◽  
Sophie C Stratton ◽  
David A van Doorn ◽  
Isabelle D Kalmar ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Dietary Protein ◽  
Protein Intake ◽  
Muscle Protein ◽  
Mtor Pathway ◽  
Protein Supplement ◽  
Protein Meal ◽  
Pathway Activation ◽  
Dose Dependent

Abstract Activation of the mechanistic target of rapamycin (mTOR)-controlled anabolic signaling pathways in skeletal muscle of rodents and humans is responsive to the level of dietary protein supply, with maximal activation and rates of protein synthesis achieved with 0.2 to 0.4 g protein/kg body weight (BW). In horses, few data are available on the required level of dietary protein to maximize protein synthesis for maintenance and growth of skeletal muscle. To evaluate the effect of dietary protein level on muscle mTOR pathway activation, five mares received different amounts of a protein supplement that provided 0, 0.06, 0.125, 0.25, or 0.5 g of crude protein (CP)/kg BW per meal in a 5 × 5 Latin square design. On each sample day, horses were fasted overnight and were fed only their protein meal the following morning. A preprandial (0 min) and postprandial (90 min) blood sample was collected and a gluteus medius muscle sample was obtained 90 min after feeding the protein meal. Blood samples were analyzed for glucose, insulin, and amino acid concentrations. Activation of mTOR pathway components (mTOR and ribosomal protein S6 [rpS6]) in the muscle samples was measured by Western immunoblot analysis. Postprandial plasma glucose (P = 0.007) and insulin (P = 0.09) showed a quadratic increase, while total essential amino acid (P < 0.0001) concentrations increased linearly with the graded intake of the protein supplement. Activation of mTOR (P = 0.02) and its downstream target, rpS6 (P = 0.0008), increased quadratically and linearly in relation to the level of protein intake, respectively. Comparisons of individual doses showed no differences (P > 0.05) between the 0.25 and 0.5 g of protein intake for either mTOR or rpS6 activation, indicating that protein synthesis may have reached near maximal capacity around 0.25 g CP/kg BW. This is the first study to show that the activation of muscle protein synthetic pathways in horses is dose-dependent on the level of protein intake. Consumption of a moderate dose of high-quality protein resulted in near maximal muscle mTOR pathway activation in mature, sedentary horses.

Abstract P111: Rheb-mTOR Signaling Pathway Regulates Cardiomyocyte Mass During Post-Neonatal Period

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Takahito Tamai ◽  
Shungo Hikoso ◽  
Tomokazu Murakawa ◽  
Jota Oyabu ◽  
Takafumi Oka ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Neonatal Period ◽  
Contractile Function ◽  
Microscopic Analysis ◽  
Mrna Translation ◽  
Premature Death ◽  
Mtor Pathway ◽  
Heart Weight ◽  
Electron Microscopic ◽  
Cross Sectional

Rheb (Ras homologue enriched in brain) is a major activator of mTOR. Rheb-mTOR pathway is a critical mechanism for maintenance of homeostasis, cell growth and stress response by regulating both protein synthesis and degradation. In this study, we attempted to clarify the role of Rheb-mTOR pathway in the heart using cardiac-specific Rheb-deficient mice (Rheb −/− ). We generated floxed Rheb mice and crossed them with transgenic mice expressing Cre recombinase in cardiac-specific mannner to generate Rheb −/− . Rheb −/− were born in Mendelian ratio, but they started to die 8 days after birth and all of them had died until 10 days after birth. Echocardiographic analysis revealed that chamber dimension and contractile function of Rheb −/− were indistinguishable from those of control mice (Rheb +/+ ) 5 days after birth. However, Rheb −/− exhibited cardiac dilatation and reduced contractility 8 days after birth (LV end diastolic dimension, Rheb −/− : 2.5±0.2 mm vs. Rheb +/+ : 2.1±0.2 mm, p<0.01, fractional shortening, Rheb −/− : 19.7 ± 9.7 % vs. Rheb +/+ : 48.6 ± 8.8 %, p<0.01). These suggest that Rheb −/− died of cardiac dysfunction and heart failure. Heart weight and cross-sectional area of cardiomyocytes were significantly lower in Rheb −/− 8 days after birth. Electron microscopic analysis revealed that the area of sarcomere was significantly lower in Rheb −/− cardiomyocytes. Expressions of sarcomeric proteins, such as myosin heavy chain, actin or desmin, were decreased in Rheb −/− , while the mRNA expression of desmin was significantly increased in Rheb −/− . Thus impairment of cardiomyocyte growth observed in Rheb −/− could be due to either increased degradation or decreased translation. Although autophagic activity was enhanced in Rheb −/− heart, ablation of Atg5, an essential molecule for autophagy, could not prevent premature death of Rheb −/− . On the other hand, polysome analysis revealed that the mRNA translation activity had decreased in Rheb −/− heart compared with Rheb +/+ . Thus, we concluded that Rheb-mTOR pathway in the heart is essential to regulate mRNA translation activity and protein synthesis, thereby to cardiomyocyte growth in neonatal period.

Abstract 274: Expression and Phosphorylation States of Eukaryotic Elongation Factor 2 (EEF2) and EEF2 Kinase in Cardiomyocytes From Hypertrophy Models

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Satoshi Kameshima ◽  
Muneyoshi Okada ◽  
Shiro Ikeda ◽  
Yuki Watanabe ◽  
Hideyuki Yamawaki
Keyword(s):  
Protein Synthesis ◽  
Cardiac Hypertrophy ◽  
Elongation Factor ◽  
Protein Translation ◽  
Cardiomyocyte Hypertrophy ◽  
Specific Substrate ◽  
Elongation Factor 2 ◽  
Eukaryotic Elongation Factor 2 ◽  
Eukaryotic Elongation Factor ◽  
Eef2 Kinase

Eukaryotic elongation factor 2 (eEF2) kinase (eEF2K, also known as calmodulin (CaM)-dependent protein kinase III) is regulated by both CaM-dependent and -independent mechanisms. Activated eEF2K phosphorylates and inactivates a specific substrate, eEF2. eEF2 activation facilitates protein translation. It is recognized that increased protein synthesis is one of the primary factors for cardiomyocyte hypertrophy. In fact, angiotensin II, which induces cardiomyocyte hypertrophy, was reported to facilitate eEF2 dephosphorylation (activation) and protein synthesis in rat isolated cardiomyocytes. We have previously demonstrated that protein expression of eEF2K was increased specifically in left ventricles (LV) of spontaneously hypertensive rats (SHR). However, expression and phosphorylation states of eEF2K and eEF2 in LV of other cardiac hypertrophy models are unknown. The aim of this study was to explore it. Male C57BL/6NJcl mice and Wistar rats received transverse aortic constriction (TAC) and isoproterenol (5 mg/kg; ISO) injection, respectively, which induced cardiac hypertrophy. After 3 and 28 days from TAC operation and 7 days from ISO injection, LV were isolated and used for Western blotting (WB) and immunohistochemistry (IHC). Echocardiography was done in TAC mice before LV isolation. In TAC-induced hypertrophied LV (3 days), eEF2K expression was significantly increased (p<0.01 vs. SHAM) and its phosphorylation at Ser366 was significantly decreased (p<0.05 vs. SHAM). Consistently, eEF2 phosphorylation was significantly increased (p<0.01 vs. SHAM). In LV from ISO rats, eEF2K phosphorylation at Ser366 was significantly decreased as determined by WB (p<0.01 vs. control). In addition, eEF2K- and phosphorylated eEF2-positive cardiomyocytes were increased as determined by IHC. These changes were also confirmed in LV from SHR. At 28 days after TAC, fractional shortening was significantly decreased (from 56.6±1.6% to 44.4±2.3%, p<0.01). Interestingly, eEF2 phosphorylation in LV was significantly decreased (p<0.05 vs. SHAM). The present results suggest the potential role of eEF2K/eEF2 signals in the pathogenesis of cardiac hypertrophy/failure.

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