scholarly journals Impact of PCSK9 on CTRP9-Induced Metabolic Effects in Adult Rat Cardiomyocytes

2021 ◽  
Vol 12 ◽  
Author(s):  
Susanne Rohrbach ◽  
Ling Li ◽  
Tatyana Novoyatleva ◽  
Bernd Niemann ◽  
Fabienne Knapp ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Fatty Acid ◽  
Protein Kinase ◽  
Glucose Metabolism ◽  
Protein Expression ◽  
Mitochondrial Biogenesis ◽  
Metabolic Effects ◽  
Lipid Lowering ◽  
Rat Cardiomyocytes ◽  
Adult Rat

The adipocytokine adiponectin and its structural homologs, the C1q/TNF-related proteins (CTRPs), increase insulin sensitivity, fatty acid oxidation and mitochondrial biogenesis. Adiponectin- and CTRP-induced signal transduction has been described to involve the adiponectin receptors and a number of co-receptors including the Low density lipoprotein receptor-related protein 1 (LRP1). LRP1 is another target of the proprotein convertase subtilisin/kexin-9 (PCSK9) in addition to the LDL-receptor (LDL-R). Here, we investigated the influence of PCSK9 on the metabolic effects of CTRP9, the CTRP with the highest homology to adiponectin. Knockdown of LRP1 in H9C2 cardiomyoblasts blunts the effects of CTRP9 on signal transduction and mitochondrial biogenesis, suggesting its involvement in CTRP9-induced cellular effects. Treatment of adult rat cardiomyocytes with recombinant PCSK9 but not knockdown of endogenous PCSK9 by siRNA results in a strong reduction in LRP1 protein expression and subsequently reduces the mitochondrial biogenic effect of CTRP9. PCSK9 treatment (24 h) blunts the effects of CTRP9-induced signaling cascade activation (AMP-dependent protein kinase, protein kinase B). In addition, the stimulating effects of CTRP9 on cardiomyocyte mitochondrial biogenesis and glucose metabolism (GLUT-4 translocation, glucose uptake) are largely blunted. Basal fatty acid (FA) uptake is strongly reduced by exogenous PCSK9, although protein expression of the PCSK9 target CD36, the key regulator of FA transport in cardiomyocytes, is not altered. In addition, only minor effects of PCSK9 were observed on CTRP9-induced FA uptake or the expression of genes involved in FA metabolism or uptake. Finally, this CTRP9-induced increase in CD36 expression occurs independent from LRP1 and LDL-R. In conclusion, PCSK9 treatment influences LRP1-mediated signaling pathways in cardiomyocytes. Thus, therapeutic PCSK9 inhibition may provide an additional benefit through stimulation of glucose metabolism and mitochondrial biogenesis in addition to the known lipid-lowering effects. This could be an important beneficial side effect in situations with impaired mitochondrial function and reduced metabolic flexibility thereby influencing cardiac function.

Modification of Ca2+-handling in cardiomyocytes by redox sensitive mechanisms in response to ouabain

2013 ◽  
Vol 91 (1) ◽  
pp. 45-55 ◽  
Author(s):  
Harjot K. Saini-Chohan ◽  
Larry Hryshko ◽  
Yan-Jun Xu ◽  
Naranjan S. Dhalla
Keyword(s):  
Signal Transduction ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Protein Kinases ◽  
Redox Status ◽  
Rat Cardiomyocytes ◽  
Adult Rat ◽  
Kinase C ◽  
Transduction Mechanisms

We examined the role of redox-sensitive signal transduction mechanisms in modifying the changes in [Ca2+]i produced by ouabain upon incubating adult rat cardiomyocytes with antioxidants or inhibitors of different protein kinases and monitoring alterations in fura-2 fluorescence. Ouabain increased basal [Ca2+]i, augmented the KCl-induced increase in [Ca2+]i, and promoted oxyradical production in cardiomyocytes. These actions of ouabain were attenuated by an oxyradical scavenging mixture (superoxide dismutase plus catalase), and the antioxidants (N-acetyl-l-cysteine and N-(2-mercaptoproprionyl)glycine). An inhibitor of MAP kinase (PD98059) depressed the ouabain-induced increase in [Ca2+], whereas inhibitors of tyrosine kinase (tyrphostin and genistein) and PI3 kinase (Wortmannin and LV294002) enhanced the ouabain-induced increase in [Ca2+]i. Inhibitors of protein kinase C (calphostin and bisindolylmalaimide) augmented the ouabain-induced increase in [Ca2+]i, whereas stimulation of protein kinase C by a phorbol ester (phorbol 12-myristate 13-acetate) depressed the action of ouabain. These results suggest that ouabain-induced inhibition of Na +–K+ ATPase may alter the redox status of cardiomyocytes through the production of oxyradicals, and increase the activities of various protein kinases. Thus, these redox-sensitive signal transduction mechanisms involving different protein kinases may modify Ca2+-handling sites in cardiomyocytes and determine the magnitude of net increase in [Ca2+]i in response to ouabain.

scholarly journals mTOR Inhibitor Therapy and Metabolic Consequences: Where Do We Stand?

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Aleksandra Kezic ◽  
Ljiljana Popovic ◽  
Katarina Lalic
Keyword(s):  
Protein Kinase ◽  
Glucose Metabolism ◽  
Calorie Restriction ◽  
Mtor Inhibitor ◽  
Hepatic Glucose Production ◽  
Mtor Inhibitors ◽  
Glucose Production ◽  
Metabolic Effects ◽  
Solid Organ ◽  
Amp Activated Protein Kinase

mTOR (mechanistic target of rapamycin) protein kinase acts as a central integrator of nutrient signaling pathways. Besides the immunosuppressive role after solid organ transplantations or in the treatment of some cancers, another promising role of mTOR inhibitor as an antiaging therapeutic has emerged in the recent years. Acute or intermittent rapamycin treatment has some resemblance to calorie restriction in metabolic effects such as an increased insulin sensitivity. However, the chronic inhibition of mTOR by macrolide rapamycin or other rapalogs has been associated with glucose intolerance and insulin resistance and may even provoke type II diabetes. These metabolic adverse effects limit the use of mTOR inhibitors. Metformin is a widely used drug for the treatment of type 2 diabetes which activates AMP-activated protein kinase (AMPK), acting as calorie restriction mimetic. In addition to the glucose-lowering effect resulting from the decreased hepatic glucose production and increased glucose utilization, metformin induces fatty acid oxidations. Here, we review the recent advances in our understanding of the metabolic consequences regarding glucose metabolism induced by mTOR inhibitors and compare them to the metabolic profile provoked by metformin use. We further suggest metformin use concurrent with rapalogs in order to pharmacologically address the impaired glucose metabolism and prevent the development of new-onset diabetes mellitus after solid organ transplantations induced by the chronic rapalog treatment.

scholarly journals Des-Acyl Ghrelin Has Specific Binding Sites and Different Metabolic Effects from Ghrelin in Cardiomyocytes

Endocrinology ◽  
2010 ◽  
Vol 151 (7) ◽  
pp. 3286-3298 ◽  
Author(s):  
Pamela V. Lear ◽  
María J. Iglesias ◽  
Sandra Feijóo-Bandín ◽  
Diego Rodríguez-Penas ◽  
Ana Mosquera-Leal ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Binding Sites ◽  
Specific Binding ◽  
Fatty Acid Uptake ◽  
Chain Fatty Acid ◽  
Metabolic Effects ◽  
Acid Uptake ◽  
Rat Cardiomyocytes ◽  
Medium Chain ◽  
Specific Binding Sites

The current study aimed to compare the effects of the peptide hormone ghrelin and des-G, its unacylated isoform, on glucose and fatty acid uptake and to identify des-G-specific binding sites in cardiomyocytes. In the murine HL-1 adult cardiomyocyte line, ghrelin and des-G had opposing metabolic effects: des-G increased medium-chain fatty acid uptake (BODIPY fluorescence intensity), whereas neither ghrelin alone nor in combination with des-G did so. Ghrelin inhibited the increase in glucose uptake normally induced by insulin (rate of 2-[3H]deoxy-d-glucose incorporation), but des-G did not; des-G was also able to partially reverse the inhibitory effect of ghrelin. In HL-1 cells and primary cultures of neonatal rat cardiomyocytes, des-G but not ghrelin increased insulin-induced translocation of glucose transporter-4 from nuclear to cytoplasmic compartments (immunohistochemistry and quantitative confocal analysis). AKT was phosphorylated by insulin but not affected by ghrelin or des-G, whereas neither AMP-activated protein kinase nor phosphatase and tensin homolog deleted from chromosome 10 was phosphorylated by any treatments. HL-1 and primary-cultured mouse and rat cardiomyocytes each possessed two independent specific binding sites for des-G not recognized by ghrelin (radioreceptor assays). Neither ghrelin nor des-G affected viability (dimethylthiazol diphenyltetrazolium bromide assays), whereas both isoforms were equally protective against apoptosis. Therefore, in cardiomyocytes, des-G binds to specific receptors and has effects on glucose and medium-chain fatty acid uptake that are distinct from those of ghrelin. Real-time PCR indicated that expression levels of ghrelin O-acyltransferase RNA were comparable between HL-1 cells, human myocardial tissue, and human and murine stomach tissue, indicating the possibility of des-G conversion to ghrelin within our model.

scholarly journals Increased Insulin Sensitivity by High-Altitude Hypoxia in Mice with High-Fat Diet-Induced Obesity Is Associated with Activated AMPK Signaling and Subsequently Enhanced Mitochondrial Biogenesis in Skeletal Muscles

Obesity Facts ◽  
2020 ◽  
Vol 13 (5) ◽  
pp. 455-472
Author(s):  
Kang Song ◽  
Yifan Zhang ◽  
Qin Ga ◽  
Zhenzhong Bai ◽  
Ri-Li Ge
Keyword(s):  
Fatty Acid ◽  
Insulin Sensitivity ◽  
Protein Kinase ◽  
High Altitude ◽  
Mitochondrial Biogenesis ◽  
High Fat Diet ◽  
Skeletal Muscles ◽  
Acid Oxidation ◽  
High Fat ◽  
Low Altitude

<b><i>Background:</i></b> This study aimed to investigate whether and how high altitude-associated ambient hypoxia affects insulin sensitivity in mice fed a high-fat diet (HFD). <b><i>Methods:</i></b> Mice were randomly divided into a control group (with normal diet feeding and low-altitude housing), LA/HFD group (with HFD feeding and low-altitude housing), and HA/HFD group (with HFD feeding and high-altitude housing). <b><i>Results:</i></b> After 8 weeks, mice in the HA/HFD group showed improved insulin sensitivity-related indices compared with the LA/HFD group. In mice residing in a low-altitude region, HFD significantly impaired mitochondrial respiratory function and mitochondrial DNA content in skeletal muscles, which was partially reversed in mice in the HA/HFD group. In addition, the fatty acid oxidation-related enzyme gene <i>CPT1</i> (carnitine palmitoyltransferase 1) and genes related to mitochondrial biogenesis such as peroxisome proliferator-activated receptor-γ coactivator-1α (<i>PGC-1α</i>), nuclear respiratory factor 1 (<i>NRF1</i>), and mitochondrial transcription factor A (<i>Tfam</i>) were upregulated in the skeletal muscles of mice housed at high altitude, in comparison to in the LA/HFD group. Furthermore, AMPK (adenosine monophosphate-activated protein kinase) signaling was activated in the skeletal muscles, as evidenced by a higher expression of phosphorylated AMPK (p-AMPK) and protein kinase B (p-AKT) in the HA/HFD group than in the LA/HFD group. <b><i>Conclusion:</i></b> Our study suggests that high-altitude hypoxia improves insulin sensitivity in mice fed an HFD, which is associated with AMPK activation in the skeletal muscle and consequently enhanced mitochondrial biogenesis and fatty acid oxidation. This work provides a molecular explanation for why high altitude is associated with a reduced incidence of insulin resistance in the obese population.

scholarly journals Autophagy and protein kinase C are required for cardioprotection by sulfaphenazole

2010 ◽  
Vol 298 (2) ◽  
pp. H570-H579 ◽  
Author(s):  
Chengqun Huang ◽  
Wayne Liu ◽  
Cynthia N. Perry ◽  
Smadar Yitzhaki ◽  
Youngil Lee ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Enhanced Recovery ◽  
Ischemia Reperfusion ◽  
Dominant Negative ◽  
Rat Cardiomyocytes ◽  
Adult Rat ◽  
Kinase C ◽  
Rat Hearts

Previously, we showed that sulfaphenazole (SUL), an antimicrobial agent that is a potent inhibitor of cytochrome P4502C9, is protective against ischemia-reperfusion (I/R) injury (Ref. 15 ). The mechanism, however, underlying this cardioprotection, is largely unknown. With evidence that activation of autophagy is protective against simulated I/R in HL-1 cells, and evidence that autophagy is upregulated in preconditioned hearts, we hypothesized that SUL-mediated cardioprotection might resemble ischemic preconditioning with respect to activation of protein kinase C and autophagy. We used the Langendorff model of global ischemia to assess the role of autophagy and protein kinase C in myocardial protection by SUL during I/R. We show that SUL enhanced recovery of function, reduced creatine kinase release, decreased infarct size, and induced autophagy. SUL also triggered PKC translocation, whereas inhibition of PKC with chelerythrine blocked the activation of autophagy in adult rat cardiomyocytes. In the Langendorff model, chelerythrine suppressed autophagy and abolished the protection mediated by SUL. SUL increased autophagy in adult rat cardiomyocytes infected with GFP-LC3 adenovirus, in isolated perfused rat hearts, and in mCherry-LC3 transgenic mice. To establish the role of autophagy in cardioprotection, we used the cell-permeable dominant-negative inhibitor of autophagy, Tat-Atg5K130R. Autophagy and cardioprotection were abolished in rat hearts perfused with recombinant Tat-Atg5K130R. Taken together, these studies indicate that cardioprotection mediated by SUL involves a PKC-dependent induction of autophagy. The findings suggest that autophagy may be a fundamental process that enhances the heart's tolerance to ischemia.

scholarly journals Synergistic Epithelial Responses to Endotoxin and a Naturally Occurring Muramyl Peptide

2000 ◽  
Vol 68 (3) ◽  
pp. 1235-1242 ◽  
Author(s):  
Tod A. Flak ◽  
Linda N. Heiss ◽  
Jacquelyn T. Engle ◽  
William E. Goldman
Keyword(s):  
Nitric Oxide ◽  
Signal Transduction ◽  
Protein Kinase ◽  
Epithelial Cells ◽  
Dna Synthesis ◽  
Metabolic Effects ◽  
Dependent Protein Kinase ◽  
Naturally Occurring ◽  
Muramyl Peptide ◽  
Dependent Protein

ABSTRACT We have investigated the synergistic interactions of a naturally occurring peptidoglycan fragment (muramyl peptide) and bacterial endotoxin in the induction of inflammatory processes within respiratory epithelial cells, at the levels of both signal transduction events and ultimate cellular metabolic effects. The source of the muramyl peptide is Bordetella pertussis, the causative agent of the respiratory disease pertussis. During log-phase growth, B. pertussis releases the muramyl peptide tracheal cytotoxin (TCT), which has the structureN - acetylglucosaminyl - 1,6 - anhydro - N - acetylmuramyl - (l) - alanyl - γ - (d) - glutamyl - meso - diaminopimelyl - (d) - alanine, equivalent to a monomeric subunit of gram-negative bacterial peptidoglycan. When applied to hamster trachea epithelial (HTE) cells, TCT and endotoxin were found to be highly synergistic in the induction of interleukin-1α (IL-1α), type II (inducible) nitric oxide synthase (iNOS), nitric oxide production, and inhibition of DNA synthesis. Neither molecule alone significantly triggered these responses. The serine/threonine protein kinase inhibitor H7 blocked induction of both IL-1α and iNOS. More selective inhibitors of protein kinase C, cyclic AMP-dependent protein kinase, and cyclic GMP-dependent protein kinase were not capable of blocking the effects of TCT and endotoxin, suggesting that the H7-inhibited component in this pathway is not among the commonly described kinase targets of H7. Treatment of HTE cells with exogenous IL-1 reproduced the induction of iNOS and DNA synthesis inhibition caused by TCT and endotoxin. H7 was not capable of interfering with effects caused by exogenous IL-1, implying that the H7-sensitive step in the pathway is upstream of IL-1 protein production. Similar assays with the phorbol ester phorbol myristate acetate indicate that it could effectively synergize with endotoxin but not with TCT, suggesting that TCT and endotoxin induce different signal transduction events that combine synergistically. The synergy observed with TCT and endotoxin in epithelial cells is significantly different from their interaction with other cell types, revealing a unique inflammatory response by epithelial cells to these natural bacterial products.

PKC-independent signal transduction pathways increase SERCA2 expression in adult rat cardiomyocytes

2005 ◽  
Vol 39 (6) ◽  
pp. 911-919 ◽  
Author(s):  
Attia Anwar ◽  
Gerhild Taimor ◽  
Hüdayi Korkususz ◽  
Rolf Schreckenberg ◽  
Tobias Berndt ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Signal Transduction Pathways ◽  
Rat Cardiomyocytes ◽  
Adult Rat
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