Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent molecular genetic investigations of primary cardiac tumors (myxomas, lipomas, rhabdomyomas, and fibromas) have provided insight into fundamental mechanisms of cardiac cell growth. Myxomas are the most common adult cardiac tumor, and familial cardiac myxomas are now appreciated to be caused by mutations in the PRKAR1alpha gene that encodes a regulatory subunit of protein kinase A. Cytogenetic studies have targeted candidate chromosomal loci that may be perturbed during cardiac lipoma pathogenesis. Rhabdomyomas, the most common pediatric cardiac neoplasm, are frequently associated with tuberous sclerosis, caused by mutations in the TSC-1 and TSC-2 genes. The study of Gorlin syndrome has shed light on the etiology of cardiac fibromas. This disorder is caused by mutation of the PTC gene, which regulates cell growth, commitment and differentiation. In the future, manipulation of PRKAR1alpha-, TSC-, and PTC-dependent pathways may foster new strategies to regenerate myocardium in the ischemic or myopathic heart.
Curr Opin Cardiol 2001 May
PMID:Tumors and the heart: molecular genetic advances. 1135 16

beta -adrenergic agonists stimulate neonatal rat cardiac fibroblast growth, albeit the identity of the signaling event(s) remains equivocal. Isoproterenol (ISO) treatment increased intracellular cyclic AMP levels; however, cyclic AMP-elevating agents had no effect on protein synthesis. The tyrosine kinase inhibitor tyrphostin A25, and the inhibition of ras processing by the farnesyltransferase inhibitor BMS-191563 attenuated ISO-stimulated protein synthesis. Concomitant with increased protein synthesis, ISO stimulated extracellular signal-regulated protein kinase (ERK) and phosphatidylinositol 3-kinase (PI3-K) activity. The MEK1/2 inhibitor PD098059 abrogated ISO-stimulated ERK activity, albeit the increase in protein synthesis was unaffected. By contrast, LY294002 inhibited both ISO-stimulated PI3-K activity, and protein synthesis. ISO treatment did not increase the expression of transforming growth factor-beta(1)(TGF-beta(1)) mRNA, whereas a significant decrease in the steady-state mRNA level of TGF- beta(3)was observed. This latter effect was mimicked by cyclic AMP-elevating agents. Angiotensin II (AII) activation of the AT(1)receptor increased protein synthesis, but in contrast to ISO, the growth response was not inhibited by either tyrphostin A25 or BMS-191563, and was associated with the concomitant expression of both TGF-beta(1)and TGF-beta(3)mRNAs. Analogous to ISO, AII treatment increased ERK and PI3-K activity, and PI3-K was required for protein synthesis. These findings are the first to highlight the activation of PI3-K by a Gs(alpha)-coupled receptor, and its essential role in beta -adrenergic as well as AT(1)receptor-mediated protein synthesis in neonatal rat cardiac fibroblasts. However, despite the conserved role of PI3-K, additional disparate signaling pathways are recruited by ISO and AII, which may differentially influence fibroblast phenotype.
J Mol Cell Cardiol 2001 Jun
PMID:beta-Adrenergic stimulation of rat cardiac fibroblasts promotes protein synthesis via the activation of phosphatidylinositol 3-kinase. 1144 12

We have shown that cGMP-dependent protein kinase (PKG) mediates stimulation of L-type calcium current by cGMP in rabbit atrial myocytes. The human atrium may have similar PKG-dependent regulation of calcium current. To elucidate the significance of PKG in cardiac function, we have isolated human PKG type I alpha cDNA (+1 to 2016), determined the nucleotide sequence and analyzed specific expression of PKG in human atrium. We obtained full-length cDNA of PKG type I alpha from human atrial RNA using reverse transcriptase-polymerase chain reaction (RT-PCR). The coding region of human cardiac PKG I alpha showed 99.9% homology to previously published human PKG I alpha except for base No. 1983. At this position G was substituted for T and this resulted in an amino acid substitution from Leu649 to Phe649. The cloned PKG I alpha cDNA was expressed in COS cells and the expressed PKG showed cGMP-stimulated PKG enzyme activity and immunoreactivity. Ribonuclease protection assay, Western blot analysis, and PKG enzyme activity assays in homogenates from human atrial tissue demonstrated the presence of PKG mRNA and protein in human atrial tissue. Immunofluorescence staining confirmed that PKG is highly expressed in human atrial myocytes. These findings suggest that PKG is highly expressed in human atrium and that PKG-dependent phosphorylation may be important in regulation of calcium channel activity in human atrial myocytes.
J Mol Cell Cardiol 2001 Aug
PMID:Expression of cGMP-dependent protein kinase in human atrium. 1144 35

Cardiac hypertrophy is one of the serious complications which increase mortality due to cardiovascular diseases. However, only a partial reduction of cardiac hypertrophy has been successful using current drug therapy. We demonstrate here reduction of cardiac hypertrophy in vitro and in vivo using an adenovirus vector encoding cyclin-dependent kinase (cdk) inhibitor p16INK4a. Adenovirus-mediated overexpression of cdk inhibitor p16INK4a completely inhibited cardiac myocyte hypertrophy induced by endothelin (ET)-1, as evaluated by [3H]leucine incorporation into the cells and mRNA levels of skeletal alpha -actin (SK-A) or atrial natriuretic peptide (ANP) as well as by morphometric analyses. We then evaluated whether p16INK4a can suppress left-ventricular (LV) hypertrophy induced by aortic banding (AOB) in rats. Catheter-mediated gene transfer of AxCAp16 was performed according to the method reported by Hajjar et al. LV overload was produced by coarctation of the ascending aorta immediately after inoculation of the heart with adenovirus. Two weeks after the procedure, the left ventricular weight/body weight ratio (LVW/BW) increased in the AOB+LacZ group in comparison to that in controls. However, LVW/BW was identical in the AOB+p16 group and controls. Histologic analysis revealed that p16INK4a inhibited hypertrophy of cardiac myocytes. These results suggest that G1 cell cycle regulators may restrict cardiac hypertrophy, and offer a novel strategy for the gene therapy of cardiac hypertrophy.
J Mol Cell Cardiol 2001 Aug
PMID:Overexpression of cdk Inhibitor p16INK4a by adenovirus vector inhibits cardiac hypertrophy in vitro and in vivo: a novel strategy for the gene therapy of cardiac hypertrophy. 1160 19

Short duration exposure to cellular stresses have been shown to activate p38 mitogen-activated protein kinase (MAPK) in cultured rat ventricular cardiomyocytes and isolated perfused hearts; however, effects of chronic stress on p38 MAPK are not well understood. This study determined whether alterations in the p38 MAPK pathway occurred prior to end-stage human heart failure. The p38 MAPK alpha isoform was detectable in human cardiac tissue. However, carefully controlled analysis of protein and message in this study demonstrated an absence of the p38 MAPK beta -isoform. Low levels of message for the non-SB203580 sensitive p38 MAPK gamma and delta isoforms were also detected in both normal and failing human myocardium. Ischemic and idiopathic end-stage failing human hearts were compared to non-failing hearts for both p38 alpha MAPK protein level and total p38 MAPK activity. Western blotting techniques demonstrated no significant changes in total p38 alpha MAPK content. However, approximately 75% decreases in active/phosphorylated p38 MAPK (P<0.005) were observed in both ischemic and idiopathic failing hearts compared to non-failing hearts. In-gel kinase assays confirmed that activated p38 MAPK, detected by Western blotting, phosphorylated its potential downstream targets. When compared to non-failing hearts, approximately 46% decreases in p38 MAPK phosphorylation of mitogen-activated protein kinase-activated protein kinase-2 (MAPKAPK-2) were observed in ischemic and idiopathic failing hearts (P=0.03 and P=0.04 respectively). Active p38 MAPK was localized to sarcomeric structures in the cytosol of myocytes by confocal immunofluorescence microscopy. The correlation between decreased MAPKAPK-2 phosphorylation and loss of active p38 MAPK in failing human myocytes suggests that decreases in the activation of p38 MAPK alpha, the predominant cardiac isoform, occur prior to end-stage heart failure.
J Mol Cell Cardiol 2001 Aug
PMID:Decreased p38 MAPK activity in end-stage failing human myocardium: p38 MAPK alpha is the predominant isoform expressed in human heart. 1144 40

The protection conferred by ischemic preconditioning (PC) of myocardium occurs in a bimodal time course. The early cardioprotection wanes rapidly and is succeeded by a delayed phase of protection. This "second window" lasts for up to 72 hours, depending on species and end-point. A widely adopted paradigm for delayed PC is the following: 1) freely diffusible molecules or radicals, generated during the PC period, act in autocrine and/or paracrine manner as triggers of cellular adaptation; 2) they cause the activation of a protein kinase signal cascade; 3) the activated kinases phosphorylate important substrate proteins. In the case of delayed PC, it is thought that the phosphorylation of transcription factors, initiating the synthesis of late appearing effector proteins that promote cell survival during subsequent ischemia, may be a crucial event. Investigation of the proximal components of this sequence has altered our perceptions of several biological mediators, previously thought to be short acting, including adenosine, NO, free radicals and bradykinin. Signal transduction components include protein kinase C, tyrosine kinases and various mitogen- and stress-activated protein kinases but their patterns of regulation are complex and as yet poorly defined. Gene expression is modified in a regulated fashion to induce new proteins that promote cell repair and to protect against subsequent ischemia-reperfusion insult. It is likely that the complex nature of the preconditioning stimulus causes the activation of a variety of transcription factors, regulating a large number of target genes. So far, attention has focussed on a small number of protein products as potential distal mediators of delayed preconditioning. These include the heat shock proteins, manganese superoxide dismutase, inducible nitric oxide synthase, the ATP-sensitive potassium channel and cyclo-oxygenase-2.
Basic Res Cardiol 2001 Jul
PMID:Delayed preconditioning of myocardium: current perspectives. 1151 89

Activation of members of the mitogen-activated protein (MAP) kinase family and their downstream effectors has been proposed to play a key role in the pathogenesis of cell survival, ischaemic preconditioning, cardiac hypertrophy and heart failure. This study investigated the responses of Src kinase and multiple MAP kinases during the transition from compensated pressure-overload hypertrophy to decompensated congestive heart failure. Extracellular signal-regulated protein kinase (ERK) 1/2, p38, and Src were activated by chronic pressure-overload and their activity was sustained for 8 weeks after aortic banding. In contrast, while p90 ribosomal S6 kinase (90RSK) and big MAP kinase 1 (BMK1) were activated in compensated hypertrophy, their activities were significantly decreased in hearts with heart failure. No changes were found in C-Jun NH2 terminal kinase (JNK) activity after aortic banding. These data suggest that differential activation of MAP kinase family members may contribute to the transition from compensated to decompensated hypertrophy. We also examined acute effects of mechanical stretch on the activation of these kinases in normal and hypertrophied hearts. In the isolated coronary-perfused heart, a balloon in the left ventricle was inflated to achieve minimum end-diastolic pressure of 25 mmHg for 10-20 min. In normal guinea pig hearts, stretch activated ERK1/2, p90RSK, p38, Src, and BMK1 but not JNK. However in hypertrophied hearts, further activation of these kinases was not observed by acute mechanical stretch. Mechanical stretch-induced activation of ERK1/2 and p38 kinase in normal hearts was attenuated significantly by a protein kinase C inhibitor, chelerythrine. We demonstrate that ERK1/2, p90RSK, p38, Src, and BMK1 are activated by chronic pressure-overload and by acute mechanical stretch. These data suggest that Src, BMK1 and p90RSK play a role as novel signal transduction pathways leading to cardiac hypertrophy. In addition, the differential inhibition of p90RSK and BMK1 in hearts with congestive heart failure suggests the specific role of these two kinases to maintain cardiac function under chronic pressure-overload.
J Mol Cell Cardiol 2001 Sep
PMID:Src and multiple MAP kinase activation in cardiac hypertrophy and congestive heart failure under chronic pressure-overload: comparison with acute mechanical stretch. 1154 43

During periods of acute rejection, transplanted hearts have increased nitric oxide (NO) production and depressed contractile function. Myocytes isolated from rejecting hearts exhibit parallel increases in NO production and reduced shortening, indicating that the contractile dysfunction of the transplanted heart is intrinsic to the myocytes. We tested the hypothesis that the contractile dysfunction of the rejecting heart is due to an NO-mediated inhibition of the L-type calcium current. Ventricular myocytes isolated from rejecting rat hearts (allografts) expressed inducible nitric oxide synthase (iNOS) and produced substantially more NO than did myocytes isolated from non-rejecting rat hearts (isografts). Aminoguanidine, an inhibitor of iNOS, reduced NO production by allograft myocytes, but was without effect on NO production by isograft myocytes. In the absence of exogenous l -arginine (the precursor of NO), the calcium current was identical in allograft and isograft myocytes. In the presence of l -arginine, the calcium current was reduced in allograft myocytes compared to isograft myocytes. Superfusion of the myocytes with either aminoguanidine or KT5823 (an inhibitor of the cyclic GMP-dependent protein kinase) reversed the depression of the calcium current in allograft myocytes, but neither inhibitor had an effect on calcium current in isograft myocytes. These results indicate that increased production of NO by myocytes isolated from rejecting hearts leads to a reduction in the calcium current. This mechanism may contribute substantially to the contractile dysfunction of rejecting transplanted hearts.
J Mol Cell Cardiol 2001 Sep
PMID:Myocytes isolated from rejecting transplanted rat hearts exhibit a nitric oxide-mediated reduction in the calcium current. 1154 47

Hypertrophy is an adaptive response of the heart to myocardial injury or hemodynamic overload that may progress and contribute to cardiac decompensation and eventually to heart failure. The signaling pathways controlling this response in the cardiac myocyte are poorly understood. A data mining effort of a human failed heart cDNA library was undertaken in an effort to identify novel signaling molecules involved in cardiac hypertrophy. This effort identified a novel kinase (MLK7) homologous to the mixed lineage kinase family of proteins. The mixed lineage kinases are mitogen-activated protein kinase kinase kinases (MAPKKKs) which activate stress activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and p38 kinase pathways. They contain a catalytic domain with homology to both serine/threonine and tyrosine-specific kinases and a dual leucine zipper. MLK7 is identical to leucine zipper and sterile-alpha motif protein kinase (ZAK) through the leucine zipper domain but has a completely divergent COOH-terminus and shares approximately 40% homology with the other MLKs overall. Expression of MLK7 mRNA is most abundant in skeletal muscle and heart, with expression restricted to the cardiac myocyte. The recombinant histidine tagged MLK7 expressed and purified from insect cells exhibited serine/threonine kinase activity in vitro with myelin basic protein as substrate. When expressed in cardiac myocytes, MLK7 activated SAPK/JNK1, and ERK and p38 to a lesser extent. Additionally, MLK7 altered fetal gene expression and increased protein synthesis in cardiac myocytes. These data suggest that MLK7 is a new member of the mixed lineage kinase family that modulates cardiac SAPK/JNK pathway and may play a role in cardiac hypertrophy and progression to heart failure.
J Mol Cell Cardiol 2001 Sep
PMID:Tissue distribution and functional expression of a cDNA encoding a novel mixed lineage kinase. 1154 52

Endothelin-1 (Et-1) is a peptide synthesized by endothelial cells (ECs) both in culture and in vivo. Cyclic strain induces gene expression of Et-1, however, the molecular mechanisms remain unclear. Since cyclic strain induces a sustained increase in intracellular reactive oxygen species (ROS), we hypothesized that the ROS could be a modulator in strain-induced Et-1 gene expression. Human umbilical vein ECs (HUVECs) subjected to cyclic strain had increased Et-1 secretion. Pretreatment of HUVECs with antioxidants, catalase (300 U/ml) or 1,3-dimethyl-2-thiourea (DMTU, 0.1 mm), abolished the strain-induced Et-1 release. ECs strained for 6 h had elevated Et-1 mRNA levels. In contrast, ECs treated with catalase or DMTU did not have increase Et-1 mRNA levels stimulated by cyclic strain. Bovine aortic ECs (BAECs) transfected with fusion plasmid containing Et-1 5'-flanking sequence (4.4 kb) and chloramphenicol acetyltransferase reporter gene produced a maximal Et-1 promoter activity after undergoing strain for 6 h, whereas pretreatment with catalase decreased this activity. BAECs cotransfected with a dominant negative mutant of Ras (RasN17), Raf-1 (Raf301), or catalytically inactive mutant of extracellular signal-regulated kinase (mERK2) had inhibited strain-induced Et-1 promoter activity, indicating the Ras/Raf/ERK pathway was involved; moreover, ERK phosphorylation was induced in ECs which were strained. This strain-activated ERK phosphorylation was attenuated in the presence of catalase. Functional analysis of the Et-1 promoter with site-directed mutagenesis indicates that the activator protein-1 (AP-1) binding site had to be within 143 base-pairs upstream of transcription initiation site for strain-induced promoter activity. Pretreatment of ECs with catalase also decreased the strain-induced promoter activity in the minimal construct (-143 bp). Our data demonstrate that strain-induced Et-1 gene expression is modulated by ROS via Ras/Raf/ERK signaling pathway, and indicate the responsiveness of the AP-1 binding site for strain-induced Et-1 expression.
J Mol Cell Cardiol 2001 Oct
PMID:Reactive oxygen species mediate cyclic strain-induced endothelin-1 gene expression via Ras/Raf/extracellular signal-regulated kinase pathway in endothelial cells. 1160 23


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