Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.2 (PDK1)
2,238 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Expression of the wild type alpha subunit of Gq (GqWT) in cardiomyocytes induces hypertrophy, whereas a constitutively active G alpha q subunit (GqQ209L) induces apoptosis. Akt phosphorylation increases with GqWT expression but is markedly attenuated in cardiomyocytes expressing GqQ209L or in those expressing GqWT and treated with agonist. A membrane-targeted Akt rescues GqQ209L-expressing cardiomyocytes from apoptotic cell death. In contrast, leukemia inhibitory factor fails to activate Akt or promote cell survival in these cells. Association of Akt and PDK-1 with the membrane is also diminished in GqQ209L-expressing cardiomyocytes. Phosphatidylinositol 3,4,5-trisphosphate (PIP3), the primary regulator of Akt, increases significantly in GqWT-expressing cells but not in cardiomyocytes expressing GqQ209L. Levels of phosphatidylinositol 4,5-bisphosphate (PIP2), the immediate precursor of PIP3, are also markedly lower in GqQ209L-expressing compared to control cells. Expression of a GqQ209L mutant that has diminished capacity to activate phospholipase C does not decrease PIP2 or Akt or induce apoptosis. In transgenic mice with cardiac G alpha q overexpression, heart failure and increased cardiomyocyte apoptosis develop during the peripartal period. Akt phosphorylation and PIP2 levels decrease concomitantly. Our findings suggest that an Akt-mediated cell survival pathway is compromised by the diminished availability of PIP2 elicited by pathological levels of Gq activity.
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PMID:Akt-mediated cardiomyocyte survival pathways are compromised by G alpha q-induced phosphoinositide 4,5-bisphosphate depletion. 1290 Apr 9

We employed Cre/loxP technology to generate mPDK1(-/-) mice, which lack PDK1 in cardiac muscle. Insulin did not activate PKB and S6K, nor did it stimulate 6-phosphofructo-2-kinase and production of fructose 2,6-bisphosphate, in the hearts of mPDK1(-/-) mice, consistent with PDK1 mediating these processes. All mPDK1(-/-) mice died suddenly between 5 and 11 weeks of age. The mPDK1(-/-) animals had thinner ventricular walls, enlarged atria and right ventricles. Moreover, mPDK1(-/-) muscle mass was markedly reduced due to a reduction in cardiomyocyte volume rather than cardiomyocyte cell number, and markers of heart failure were elevated. These results suggested mPDK1(-/-) mice died of heart failure, a conclusion supported by echocardiographic analysis. By employing a single-cell assay we found that cardiomyocytes from mPDK1(-/-) mice are markedly more sensitive to hypoxia. These results establish that the PDK1 signalling network plays an important role in regulating cardiac viability and preventing heart failure. They also suggest that a deficiency of the PDK1 pathway might contribute to development of cardiac disease in humans.
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PMID:Deficiency of PDK1 in cardiac muscle results in heart failure and increased sensitivity to hypoxia. 1297 Jan 79

Glucocorticoids impair insulin sensitivity. Because insulin resistance is closely linked to increased incidence of cardiovascular diseases and given that metabolic abnormalities have been linked to initiation of heart failure, we examined the acute effects of dexamethasone (DEX) on rat cardiac metabolism. Although injection of DEX for 4 h was not associated with hyperinsulinemia, the euglycemic-hyperinsulinemic clamp showed a decrease in glucose infusion rate. Rates of cardiac glycolysis were unaffected, whereas the rate of glucose oxidation following DEX was significantly decreased and could be associated with augmented expression of PDK4 mRNA and protein. Myocardial glycogen content in DEX hearts increased compared with control. Similar to hypoinsulinemia induced by streptozotocin (STZ), hearts from insulin-resistant DEX animals also demonstrated enlargement of the coronary lipoprotein lipase (LPL) pool. However, unlike STZ, DEX hearts showed greater basal release of LPL and were able to maintain their high heparin-releasable LPL in vitro. This effect could be explained by the enhanced LPL mRNA expression following DEX. Our data provide evidence that in a setting of insulin resistance, an increase in LPL could facilitate increased delivery of fatty acid to the heart, leading to excessive triglyceride storage. It has not been determined whether these acute effects of DEX on cardiac metabolism can be translated into increased cardiovascular risk.
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PMID:Single-dose dexamethasone induces whole-body insulin resistance and alters both cardiac fatty acid and carbohydrate metabolism. 1522 Feb 3

Phosphoinositide-3 kinases (PI3Ks) are a family of evolutionary conserved lipid kinases that mediate many cellular responses in both physiologic and pathophysiologic states. Class I PI3K can be activated by either receptor tyrosine kinase (RTK)/cytokine receptor activation (class I(A)) or G-protein-coupled receptors (GPCR) (class I(B)). Once activated PI3Ks generate phosphatidylinositols (PtdIns) (3,4,5)P(3) leading to the recruitment and activation of Akt/protein kinase B (PKB), PDK1 and monomeric G-proteins (e.g. Rac-GTPases), which then activate a range of downstream targets including glycogen synthase kinase-3beta (GSK-3beta), mammalian target of rapamycin (mTOR), p70S6 kinase, endothelial nitric oxide synthase (eNOS) and several anti-apoptotic effectors. Class I(A) (PI3Kalpha, beta and delta) and class I(B) (PI3Kgamma) PI3Ks mediate distinct phenotypes in the heart and under negative control by the 3'-lipid phosphatase, phosphatase and tensin homolog on chromosome ten (PTEN) which dephosphorylate PtdIns(3,4,5)P(3) into PtdIns(4,5)P(2). PI3Kalpha, gamma and PTEN are expressed in cardiomyocytes, fibroblasts, endothelial cells and vascular smooth muscle cells where they modulate cell survival/apoptosis, hypertrophy, contractility, metabolism and mechanotransduction. Several transgenic and knockout models support a fundamental role of PI3K/PTEN signaling in the regulation of myocardial contractility and hypertrophy. Consequently the PI3K/PTEN signaling pathways are involved in a wide variety of diseases including cardiac hypertrophy, heart failure, preconditioning and hypertension. In this review, we discuss the biochemistry and molecular biology of PI3K (class I isoforms) and PTEN and their critical role in cardiovascular physiology and diseases.
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PMID:The role of phosphoinositide-3 kinase and PTEN in cardiovascular physiology and disease. 1527 15

In patients with congestive heart failure, high serum levels of the proinflammatory cytokine interleukin (IL)-18 were reported. A positive correlation was described between serum IL-18 levels and the disease severity. IL-18 has also been shown to induce atrial natriuretic factor (ANF) gene expression in adult cardiomyocytes. Because re-expression of the fetal gene ANF is mostly associated with hypertrophy, a hallmark of heart failure, we hypothesized that IL-18 induces cardiomyocyte hypertrophy. Treatment of the cardiomyocyte cell line HL-1 with IL-18 induced hypertrophy as characterized by increases in protein synthesis, phosphorylated p70 S6 kinase, and ribosomal S6 protein levels as well as cell surface area. Furthermore, IL-18 induced ANF gene transcription in a time-dependent manner as evidenced by increased ANF secretion and ANF promoter-driven reporter gene activity. Investigation into possible signal transduction pathways mediating IL-18 effects revealed that IL-18 activates phosphoinositide 3-kinase (PI3K), an effect that was blocked by wortmannin and LY-294002. IL-18 induced Akt phosphorylation and stimulated its activity, effects that were abolished by Akt inhibitor or knockdown. IL-18 stimulated GATA4 DNA binding activity and increased transcription of a reporter gene driven by multimerized GATA4-binding DNA elements. Pharmacological inhibition or knockdown studies revealed that IL-18 induced cardiomyocyte hypertrophy and ANF gene transcription via PI3K, PDK1, Akt, and GATA4. Most importantly, IL-18 induced ANF gene transcription and hypertrophy of neonatal rat ventricular myocytes via PI3K-, Akt-, and GATA4-dependent signaling. Together these data provide the first evidence that IL-18 induces cardiomyocyte hypertrophy via PI3K-dependent signaling, defines a mechanism of IL-18-mediated ANF gene transcription, and further supports a role for IL-18 in inflammatory heart diseases including heart failure.
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PMID:Interleukin-18 is a pro-hypertrophic cytokine that acts through a phosphatidylinositol 3-kinase-phosphoinositide-dependent kinase-1-Akt-GATA4 signaling pathway in cardiomyocytes. 1557 30

We explored three approaches to create tissue-specific knock-in mice by generating knock-in mice in which a substrate-docking site of the PDK1 protein kinase was ablated in Cre-expressing tissues in a way that prevented activation of one of its substrates, p70 ribosomal S6 kinase (S6K), but not another (protein kinase B (PKB)). Employing two of the approaches, termed the "heterozygous" and "minigene" methods, we generated mice in which Cre-expressing skeletal and cardiac muscle produced the mutant rather than wild type PDK1. Consistent with this, injection of these mice with insulin only induced activation of PKB but not S6K in muscle tissues. We have also demonstrated that insulin-stimulated glucose uptake proceeds normally in knock-in mice, consistent with the notion that PKB mediates this process. In contrast to conditional knock-out of PDK1 in muscle, the knock-in mice did not develop dilated cardiomyopathy, suggesting that PKB plays a key role in protecting mice from heart failure. The third knock-in strategy that was evaluated, termed the "inversion" method, did not proceed with high efficiency. We discuss the merits and disadvantages of each of the conditional knock-in approaches, along with the applications for which they may be most suited, and suggest how they could be further refined.
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PMID:Evaluation of approaches to generation of tissue-specific knock-in mice. 1688 94

The heart adapts to changes in nutritional status and energy demands by adjusting its relative metabolism of carbohydrates and fatty acids. Loss of this metabolic flexibility such as occurs in diabetes mellitus is associated with cardiovascular disease and heart failure. To study the long-term consequences of impaired metabolic flexibility, we have generated mice that overexpress pyruvate dehydrogenase kinase (PDK)4 selectively in the heart. Hearts from PDK4 transgenic mice have a marked decrease in glucose oxidation and a corresponding increase in fatty acid catabolism. Although no overt cardiomyopathy was observed in the PDK4 transgenic mice, introduction of the PDK4 transgene into mice expressing a constitutively active form of the phosphatase calcineurin, which causes cardiac hypertrophy, caused cardiomyocyte fibrosis and a striking increase in mortality. These results demonstrate that cardiac-specific overexpression of PDK4 is sufficient to cause a loss of metabolic flexibility that exacerbates cardiomyopathy caused by the calcineurin stress-activated pathway.
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PMID:Overexpression of pyruvate dehydrogenase kinase 4 in heart perturbs metabolism and exacerbates calcineurin-induced cardiomyopathy. 1808 2

Pressure overload (PO) first causes cardiac hypertrophy and then heart failure (HF), which are associated with sex differences in cardiac morphology and function. We aimed to identify genes that may cause HF-related sex differences. We used a transverse aortic constriction (TAC) mouse model leading to hypertrophy without sex differences in cardiac function after 2 weeks, but with sex differences in hypertrophy 6 and 9 weeks after TAC. Cardiac gene expression was analyzed 2 weeks after surgery. Deregulated genes were classified into functional gene ontology (GO) categories and used for pathway analysis. Classical marker genes of hypertrophy were similarly upregulated in both sexes (alpha-actin, ANP, BNP, CTGF). Thirty-five genes controlling mitochondrial function (PGC-1, cytochrome oxidase, carnitine palmitoyl transferase, acyl-CoA dehydrogenase, pyruvate dehydrogenase kinase) had lower expression in males compared to females after TAC. Genes encoding ribosomal proteins and genes associated with extracellular matrix remodeling exhibited relative higher expression in males (collagen 3, matrix metalloproteinase 2, TIMP2, and TGFbeta2, all about twofold) after TAC. We confirmed 87% of the gene expression by real-time polymerase chain reaction. By GO classification, female-specific genes were related to mitochondria and metabolism and males to matrix and biosynthesis. Promoter studies confirmed the upregulation of PGC-1 by E2. Less downregulation of metabolic genes in female hearts and increased protein synthesis capacity and deregulation of matrix remodeling in male hearts characterize the sex-specific early response to PO. These differences could contribute to subsequent sex differences in cardiac function and HF.
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PMID:Sex-specific pathways in early cardiac response to pressure overload in mice. 1866 44

Shifting substrate oxidation in heart muscle from fatty acids to glucose (substrate-switch) may improve contractile function in heart failure. We tested whether application of two agents (etomoxir and NVP-LAB121) capable of inducing a substrate-switch reverts the onset of heart failure in rats with chronic pressure-overload. Hypertrophy was induced by aortic banding in rats for 1 or 15 weeks. Rats were treated for 10 days with the CPT-1-inhibitor etomoxir [29.5 micromol/(kg day)] or with NVP-LAB121 [60 micromol/(kg day)], a pyruvate-dehydrogenase-kinase-inhibitor, before assessment by echocardiography and perfusion as isolated working hearts. We also analyzed PDH- and CPT1-activity and expression of alpha- and beta-MHC by RT-PCR. Aortic banding increased heart-to-body-weight-ratio (g/kg) from 3.44 +/- 0.26 to 4.14 +/- 0.48 after 1 week and from 2.80 +/- 0.21 to 6.54 +/- 0.26 after 15 weeks. Ejection fraction was impaired after 15 weeks (57 +/- 11 vs. 73 +/- 8%, P < 0.05) and rats exhibited signs of heart failure. Total PDH activity was the same in all groups. CPT-1 activity was unchanged after 1 week but decreased after 15 weeks (P < 0.01). Neither etomoxir nor NVP-LAB121 affected cardiac function in vivo, but etomoxir improved function of the isolated heart. The drugs did not affect total PDH and CPT-1 activity, but increased PDH-activity status, prevented a decrease in PDK4 expression in heart failure, increased alpha and beta-MHC expression and shifted substrate oxidation toward glucose in the isolated working rat heart. In conclusion, pharmacologic induction of substrate-switching is associated with changes in myofibrillar isoform expression but does not reverse heart failure in vivo. The improvement of function in vitro deserves further investigation.
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PMID:The metabolic modulators, Etomoxir and NVP-LAB121, fail to reverse pressure overload induced heart failure in vivo. 1929 46

Glucocorticoids increase pyruvate dehydrogenase kinase-4 (PDK4) mRNA and protein expression, which phosphorylates pyruvate dehydrogenase, thereby preventing the formed pyruvate from undergoing mitochondrial oxidation. This increase in PDK4 expression is mediated by the mandatory presence of Forkhead box other factors (FoxOs) in the nucleus. In the current study, we examined the importance of the nongenomic effects of dexamethasone (Dx) in determining the compartmentalization of FoxO and hence its transcriptional activity. Rat cardiomyocytes exposed to Dx produced a robust decrease in glucose oxidation. Measurement of FoxO compartmentalization demonstrated increase in nuclear but resultant decrease in cytosolic content of FoxO1 with no change in the total content. The increase in nuclear content of FoxO1 correlated to an increase in nuclear phospho-p38 MAPK together with a robust association between this transcription factor and kinase. Dx also promoted nuclear retention of FoxO1 through a decrease in phosphorylation of Akt, an effect mediated by heat shock proteins binding to Akt. Measurement of the nuclear and total expression of sirtuin-1 protein showed no change after Dx. Instead, Dx increased the association of sirtuin-1 with FoxO1, thereby causing a decrease in FoxO acetylation. Manipulation of FoxO1 through agents that interfere with its nuclear shuttling or acetylation were effective in reducing Dx-induced increase in PDK4 protein expression. Our data suggest that FoxO1 has a major PDK4-regulating function. In addition, given the recent suggestions that altering glucose use can set the stage for heart failure, manipulating FoxO could assist in devising new therapeutic strategies to optimize cardiac metabolism and prevent PDK4 induced cardiac complications.
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PMID:The increase in cardiac pyruvate dehydrogenase kinase-4 after short-term dexamethasone is controlled by an Akt-p38-forkhead box other factor-1 signaling axis. 2018 97


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