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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The objective of the present study was to assess the cardioprotective effect of dual NEP-ACE inhibition in relation to endogenous cardiac bradykinin (BK), its active metabolite des-Arg9-BK, endogenous brain natriuretic peptides (BNP), and cGMP. Rats were treated with the dual metallopeptidase inhibitor, omapatrilat, or the ACE inhibitor, ramipril, for 7 d (1 mg.kg(-1).d(-1)). Hearts were then isolated and subjected to a zero-flow ischemia and reperfusion (except controls), in the absence or presence of either a B2-receptor antagonist (Hoe-140), a B1-receptor antagonist (Lys-Leu8-des-Arg9-BK), or the GC-A/GC-B-receptor antagonist (HS-142-1). Chronic omapatrilat and ramipril increased the amount of endogenous BK collected upon reperfusion, but only ramipril increased that of des-Arg9-BK. Only omapatrilat increased both peak BNP and peak cGMP upon reperfusion, those increases being blocked by Hoe-140. Chronic omapatrilat (but not ramipril) decreased the total noradrenaline and lactate dehydrogenase release during the reperfusion period. Importantly, only omapatrilat improved the functional recovery of the ischemic reperfused heart, with a reduced left ventricular end-diastolic pressure, and improved developed left ventricular pressure. All cardio protective effects of omapatrilat were blocked by Hoe-140 and by HS-142-1, but not by the B1-receptor antagonist. In conclusion, a chronic treatment with a dual metallopeptidase inhibitor demonstrated a cardioprotective action not observed with an ACE inhibitor in a context of severe ischemia in rat isolated hearts, which was mediated by both endogenous BK and BNP.
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PMID:The cardioprotective effect of dual metallopeptidase inhibition: respective roles of endogenous kinins and natriuretic peptides. 1579 Dec 90

Kinins are vasoactive peptides released from precursors called kininogens, and serum levels of both T- and K-kininogens increase dramatically as rats age. Kinin release is tightly regulated, and here we show that serum kinin levels also increase with age, from 63 +/- 16 nmol/L in young Fisher 344 rats to 398 +/- 102 nmol/L in old animals. Both K- and T-kininogens contribute sequentially to this increase, with the increase in middle-aged animals being driven primarily by K-kininogen, whereas the further augmentation in older rats occurs by increasing T-kininogen. By measuring ERK activation, we show that aorta endothelial cells from old animals are hyporesponsive to exogenous bradykinin. However, if serum kinin levels are experimentally decreased by lipopolysaccharide treatment, then the endothelial response to bradykinin is re-established. These results indicate that serum levels of kinins increase with age, whereas the responsiveness of target cells to kinins is reduced in these same animals.
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PMID:Increased kinin levels and decreased responsiveness to kinins during aging. 1612

Plasma levels of kininogens increase with age in both rats and humans. Kininogens are inhibitors of cysteine proteinases, and filarial cysteine proteinase inhibitors (cystatins) reduce the proliferation of T cells. We evaluated whether T-kininogen (T-KG) might mimic this effect, and here we present data indicating that exposure of either rat splenocytes or Jurkat cells to purified T-KG results in inhibition of both ERK activation and [(3)H]-thymidine incorporation, both basal and in response to ConA or PHA. Interestingly, T-KG did not impair [(3)H]-thymidine incorporation in response to IL-2, which requires primarily the activation of the JNK and Jak/STAT pathways. These effects were neither the consequence of increased cell death, nor required the activity of kinin receptors. Furthermore, when T cell receptor proximal events were bypassed by the use of PMA plus Calcium ionophore, T-KG no longer inhibited ERK activation, suggesting that inhibition occurs upstream of these events, possibly at the level of membrane associated signal transduction molecules. We conclude that, like filarial cystatins, T-KG inhibits ERK-dependent T cell proliferation, and these observations suggest a possible role for T-KG in immunosenescence.
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PMID:T-kininogen, a cystatin-like molecule, inhibits ERK-dependent lymphocyte proliferation. 1614 Mar 59

The cortical thick ascending limb (CTAL) coexpresses angiotensin (Ang) II/Ang III receptor type 1A (AT(1A)-R) and bradykinin (BK) receptor type 2 (B2-R). In several cell types, these two receptors share the same signaling pathways, although their physiological functions are often opposite. In CTAL, little is known about the intracellular transduction events leading to the final physiological response induced by these two peptides. We investigated and compared in this segment the action of Ang II/III and BK on intracellular calcium concentration ([Ca2+]i) response and metabolic CO2 production, an index of Na+ transport, by using inhibitors of protein kinase C (bisindolylmaleimide), Src tyrosine kinase (herbimycin A and PP2), and MAPK/ERK (PD98059 and UO126). Ang II/III and BK (10(-7) mol/liter) released Ca2+ from the same intracellular pools but activated different Ca2+ entry pathways. Ang II/III- or BK-induced [Ca2+]i increases were similarly potentiated by bisindolylmaleimide. Herbimycin A and PP2 decreased similarly the [Ca2+]i responses induced by Ang II/III and BK. In contrast, PD98059 and UO126 affected the effects of BK to a larger extent than those of Ang II/III. Especially, the Ca2+ influx induced by BK was more strongly inhibited than that induced by Ang II/III in the presence of both compounds. The Na+ transport was inhibited by BK and stimulated by Ang II/III. The inhibitory action of BK on Na+ transport was blocked by UO126, whereas the stimulatory response of Ang II/III was potentiated by UO126 but blocked by bisindolylmaleimide. These data suggest that the inhibitory effect of BK on Na+ transport seems to be directly mediated by an increase in Ca2+ influx dependent on MAPK/ERK pathway activation. In contrast, the stimulatory effect of Ang II/III on Na+ transport is more complex and involves PKC and MAPK/ERK pathways.
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PMID:Tyrosine kinase and mitogen-activated protein kinase/extracellularly regulated kinase differentially regulate intracellular calcium concentration responses to angiotensin II/III and bradykinin in rat cortical thick ascending limb. 1621 Mar 76

Rat1 fibroblasts stably transfected with the rat angiotensin II (AngII) AT1a and bradykinin (BK) B2 receptor cDNAs gained the ability to bind Ang II and BK. Wild-type Rat1 cells bound neither ligand. Exposure to either effector led to characteristic Galphai and Galphaq signal cascades, the release of arachidonic acid (ARA), and the intracellular accumulation of inositol phosphates (IP). Microarray analyses in response to BK or AngII showed that both receptors markedly induce the CCN family genes, CTGF (CCN2) and Cyr61 (CCN1), as well as the vasculature-related genes, Cnn1 and Egr1. Real time PCR confirmed the increased expression of connective tissue growth factor (CTGF) mRNA. Combined sequence-based analysis of gene promoter regions with statistical prevalence analyses identified CREB, SRF, and ATF-1, downstream targets of ERK, and JNK, as prominent products of genes that are regulated by ligand binding to the BK or AngII receptors. The binding of AngII or BK markedly stimulated the phosphorylation and thus the activation of ERK2, JNK, and p38MAPK. A BKB2R and an AT1aR chimera which displayed only negligible G-protein-related signaling were constructed. Both mutant receptors continued to activate these kinases and stimulate CTGF expression. Inhibitors of ERK1/2 and JNK but not p38MAPK inhibited the BK- and AngII-stimulated expression of CTGF in cells expressing either the WT or mutant receptors, illustrating that ERK and JNK participate in the control of CTGF expression in a manner that appears to be independent of G-protein. Conversely, addition of BK or AngII to the cell line expressing WT AT1aR and BKB2R downregulated the expression of collagen alpha1(I) (COL1A1) mRNA. However, these effectors did not have this effect in cells expressing the mutant receptors. Thus, a robust G-protein related response is necessary for BK or AngII to affect COL1A1 expression.
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PMID:Microarray and phosphokinase screenings leading to studies on ERK and JNK regulation of connective tissue growth factor expression by angiotensin II 1a and bradykinin B2 receptors in Rat1 fibroblasts. 1629 26

Basal proliferation of endothelial cells increases with age, and this might play a role in the etiology of age-related vascular diseases, as well as angiogenesis. Serum kininogen levels increase during aging in rats and humans, and T-kininogen (T-KG) can affect proliferative homeostasis in several cell models. Both kinins and kininogens have been shown previously to be angiogenic through activation of endothelial cell proliferation, and here we show that exposure of endothelial cells to T-KG results in vigorous cell proliferation, accompanied by ERK/AKT activation. In our experiments, the proliferative response requires B1 and B2 kinin receptors, even though kinins are not released from the precursor. We hypothesize that the age-related increase in T-KG could play a significant role in the age-related dysregulation of vascular physiology and function.
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PMID:T-kininogen induces endothelial cell proliferation. 1637 35

Insulin and angiotensin II are hormones that play pivotal roles in the control of two vital and closely related systems, the metabolic and the circulatory systems, respectively. A failure in the proper action of each of these hormones results, to a variable degree, in the development of two highly prevalent and commonly overlapping diseases-diabetes mellitus and hypertension. In recent years, a series of studies has revealed a tight connection between the signal transduction pathways that mediate insulin and angiotensin II actions in target tissues. This molecular cross-talk occurs at multiple levels and plays an important role in phenomena that range from the action of anti-hypertensive drugs to cardiac hypertrophy and energy acquisition by the heart. At the extracellular level, the angiotensin-converting enzyme controls angiotensin II synthesis but also interferes with insulin signaling through the proper regulation of angiotensin II and through the accumulation of bradykinin. At an early intracellular level, angiotensin II, acting through JAK-2/IRS-1/PI3-kinase, JNK and ERK, may induce the serine phosphorylation and inhibition of key elements of the insulin-signaling pathway. Finally, by inducing the expression of the regulatory protein SOCS-3, angiotensin II may impose a late control on the insulin signal. This review will focus on the main advances obtained in this field and will discuss the implications of this molecular cross-talk in the common clinical association between diabetes mellitus and hypertension.
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PMID:The multi-faceted cross-talk between the insulin and angiotensin II signaling systems. 1638 35

An angiotensin-converting enzyme inhibitor (ACE-I) reduces cardiac remodeling and a bradykinin B2 receptor (B2R) antagonist partially abolishes this ACE-I effect. However, bradykinin has two different types of receptor, the B1 receptor (B1R) and B2R. Although B1R is induced under several pathological conditions, including hypertension, the role of cardiac B1R in hypertension is not clear. We therefore investigated the role of cardiac B1R in stroke-prone spontaneously hypertensive rats (SHR-SP) and Wistar-Kyoto (WKY) rats. The B1R mRNA expression level in the heart was significantly higher in SHR-SP than in WKY rats. Chronic infusion of a B1R antagonist for 4 weeks significantly elevated blood pressure and left-ventricular weight of SHR-SP. Morphological analysis indicated that cardiomyocyte size and cardiac fibrosis significantly increased after administration of the B1R antagonist. The phosphorylation of mitogen-activated protein (MAP) kinases, including ERK, p38, and JNK, was significantly increased in the hearts of SHR-SP rats receiving the B1R antagonist. The TGF-beta1 expression level was significantly increased in SHR-SP rats treated with the B1R antagonist compared to that in WKY rats. The B1R antagonist significantly increased phosphorylation of Thr495 in endothelial nitric oxide synthase (eNOS), which is an inhibitory site of eNOS. These results suggest that the role of B1R in the heart may be attenuation of cardiac remodeling via inhibition of the expression of MAP kinases and TGF-beta1 through an increase in eNOS activity in a hypertensive condition.
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PMID:The role of bradykinin B1 receptor on cardiac remodeling in stroke-prone spontaneously hypertensive rats (SHR-SP). 1649 53

Although bradykinin has been demonstrated to protect the heart at reperfusion, the detailed cellular and molecular mechanisms that mediate the protection remain elusive. Here we aimed to determine whether bradykinin protects the heart at reperfusion by modulating the mitochondrial permeability transition pore (mPTP) opening through glycogen synthase kinase 3beta (GSK-3beta). Bradykinin given at reperfusion reduced infarct size in isolated rat hearts subjected to 30 min regional ischemia followed by 2 h of reperfusion. The infarct-limiting effect of bradykinin was reversed by atractyloside, an opener of the mPTP, suggesting that bradykinin may protect the heart at reperfusion by modulating the mPTP opening. In support of this observation, bradykinin prevented the collapse of mitochondrial membrane potential (DeltaPsi(m)), an index of the mPTP opening. Bradykinin increased GSK-3beta phosphorylation at reperfusion, and the selective inhibitor of GSK-3beta SB216763 reduced infarct size and prevented the loss of DeltaPsi(m) by mimicking the effect of bradykinin. The effect of bradykinin on GSK-3beta phosphorylation was blocked by wortmannin and LY294002, and bradykinin increased Akt phosphorylation at reperfusion. Further experiments showed that the MEK inhibitor PD98059 prevented the effect of bradykinin on GSK-3beta. However, the mTOR/p70s6K pathway inhibitor rapamycin did not alter bradykinin-induced GSK-3beta phosphorylation and bradykinin failed to alter phosphorylation of either mTOR or p70s6K at reperfusion. Taken together, these data suggest that bradykinin protects the heart at reperfusion by modulating the mPTP opening through inhibition of GSK-3beta. The PI3-kinase/Akt pathway and ERK, but not the mTOR/p70s6K pathway account for the suppression of GSK-3beta by bradykinin.
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PMID:Bradykinin prevents reperfusion injury by targeting mitochondrial permeability transition pore through glycogen synthase kinase 3beta. 1651 18

Using fura 2-loaded vessels, we tested whether ouabain modulates endothelial cytoplasmic calcium concentration ([Ca(2+)](CYT)) in rat descending vasa recta (DVR). Over a broad range between 10(-10) and 10(-4) M, ouabain elicited biphasic peak and plateau [Ca(2+)](CYT) elevations. Blockade of voltage-gated Ca(2+) entry with nifedipine did not affect the response to ouabain mitigating against a role for myo-endothelial gap junctions. Reduction of extracellular Na(+) concentration ([Na(+)](o)) or Na(+)/Ca(2+) exchanger (NCX) inhibition with SEA-0400 (10(-6) M) elevated [Ca(2+)](CYT), supporting a role for NCX in the setting of basal [Ca(2+)](CYT). SEA-0400 abolished the [Ca(2+)](CYT) response to ouabain implicating NCX as a mediator. The transient peak phase of [Ca(2+)](CYT) elevation that followed either ouabain or reduction of [Na(+)](o) was abolished by 2-aminoethoxydiphenyl borate (5 x 10(-5) M). Cation channel blockade with La(3+) (10 muM) or SKF-96365 (10 muM) also attenuated the ouabain-induced [Ca(2+)](CYT) response. Ouabain pretreatment increased the [Ca(2+)](CYT) elevation elicited by bradykinin (10(-7) M). We conclude that inhibition of ouabain-sensitive Na(+)-K(+)-ATPase enhances DVR endothelial Ca(2+) store loading and modulates [Ca(2+)](CYT) signaling through mechanisms that involve NCX, Ca(2+) release, and cation channel activation.
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PMID:Ouabain modulation of endothelial calcium signaling in descending vasa recta. 1659 12


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