Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelin-1 (ET-1) is a vasoconstrictor secreted by endothelial cells, which acts as the natural counterpart of the vasodilator nitric oxide (NO). ET-1 contributes to vascular tone and regulates cell proliferation through activation of ETA and ETB receptors. Physical factors such as shear stress, or stimuli including thrombin, epinephrine, angiotensin II, growth factors, cytokines and free radicals enhance secretion of ET-1. By contrast, mediators like nitric oxide (NO), cyclic GMP, atrial natriuretic peptide, and prostacyclin reduce the release of endogenous ET-1. Thus, under normal conditions, the effects of the ET-1 are carefully regulated through inhibition or stimulation of ET-1 release from endothelium. Endothelial dysfunction is one of the earliest landmarks of vascular abnormalities. Altered function of endothelium may result from absolute decrease in bioavailability of NO as well as from relative augment in ET-1 synthesis, release or activity. Imbalance in the production of vasodilator and vasoconstrictor agents may contribute to the onset of hemodynamic disorders. Since dysregulation of the endothelin system is important in the pathogenesis of several cardiovascular diseases, the ETA and ETB receptors are attractive therapeutic targets for disorders associated with elevated ET-1 levels. ET receptor antagonists may be regarded as disease-modifying agents thanks to their ability to preserve endothelial integrity when the endothelin system is overactive. This review summarizes the current knowledge on the role of ET-1 in experimental hypertension and describes recent findings on the involvement of MAPK signalling pathways in ET-1 release in hypertension associated with insulin resistance. Moreover, therapeutic applications of ET-1 receptor blockers are also discussed.
 ...
PMID:Endothelin-1: the yin and yang on vascular function. 1678 11

The present studies were undertaken to investigate the effect of C-atrial natriuretic peptide (ANP)(4-23) and several peptide fragments containing 12 amino acids from different regions of the cytoplasmic domain of natriuretic peptide receptor (NPR)-C on cell proliferation in the absence or presence of angiotensin (ANG) II, endothelin (ET)-1, and arginine vasopressin (AVP) in A-10 vascular smooth muscle cells (VSMC). The peptide fragments used have either complete G(i) activator sequences K(461)-H(472) (peptide 1) and H(481)-H(492) (peptide 3) or partial G(i) activator sequences R(469)-K(480) (peptide 2) and I(465)-H(472) (peptide Y) with truncated COOH or NH(2) terminus, respectively. The other peptide used had no structural specificity (Q(473)-K(480), peptide X) or was the scrambled peptide control for peptide 1 (peptide Z). ANG II, ET-1 and AVP significantly stimulated DNA synthesis in these cells as determined by [(3)H]thymidine incorporation that was inhibited by peptides 1, 2, and 3 and not by peptides X, Y, and Z in a concentration-dependent manner, with an apparent K(i) between 1 and 10 nM. In addition, C-ANP(4-23), which interacts with NPR-C, also inhibited DNA synthesis stimulated by vasoactive peptides; however, the inhibition elicited by C-ANP(4-23) was not additive with the inhibition elicited by peptide 1. On the other hand, basal DNA synthesis in these cells was not inhibited by C-ANP(4-23) or the peptide fragments. Furthermore, vasoactive peptide-induced stimulation of DNA synthesis was inhibited by PD-98059 and wortmannin, and this inhibition was potentiated by peptide 1. In addition, peptide 1 also inhibited vasoactive peptide-induced phosphorylation of ERK1/2 and AKT and enhanced expression of G(i)alpha proteins. These data suggest that C-ANP(4-23) and small peptide fragments containing 12 amino acids irrespective of the region of the cytoplasmic domain of NPR-C inhibit proliferative responses of vasoactive peptides through G(i)alpha protein and MAP kinase/phosphatidylinositol 3-kinase/AKT pathways.
 ...
PMID:Small cytoplasmic domain peptides of natriuretic peptide receptor-C attenuate cell proliferation through Gialpha protein/MAP kinase/PI3-kinase/AKT pathways. 1692 Aug 14

It is generally believed that a mechanical signal initiates a cascade of biological events leading to coordinated cardiac remodeling. 14-3-3 family members are dimeric phosphoserine-binding proteins that regulate signal transduction, apoptotic, and checkpoint control pathways. To evaluate the molecular mechanism underlying swimming stress-induced cardiac remodeling, we examined the role of 14-3-3 protein and MAPK pathway by pharmacological and genetic means using transgenic mice with cardiac-specific expression of dominant-negative (DN) mutants of 14-3-3 (DN 14-3-3/TG) and p38alpha/beta MAPK (DNp38alpha and DNp38beta) mice. p38 MAPK activation was earlier, more marked, and longer in the myocardium of the TG group compared with that of the nontransgenic (NTG) group after swimming stress, whereas JNK activation was detected on day 5 and decreased afterward. In contrast, ERK1/2 was not activated after swimming stress in either group. Cardiomyocyte apoptosis, cardiac hypertrophy, and fibrosis were greatly increased in the TG group compared with those in the NTG group. Moreover, we found a significant correlation between p38 MAPK activation and apoptosis in the TG group. Furthermore, DN 14-3-3 hearts showed enhanced atrial natriuretic peptide expression. In contrast, DNp38alpha and DNp38beta mice exhibited reduced mortality and increased resistance to cardiac remodeling after 28 days of swimming stress compared with TG and NTG mice. Besides, treatment with a p38 MAPK inhibitor, FR-167653, resulted in regression of cardiac hypertrophy and fibrosis and improvement in the survival rate in the TG group. These results indicate for the first time that 14-3-3 protein along with p38 MAPK plays a crucial role in left ventricular remodeling associated with swimming stress.
 ...
PMID:Swimming stress in DN 14-3-3 mice triggers maladaptive cardiac remodeling: role of p38 MAPK. 1704 Sep 71

Fully grown mammalian oocytes resume meiosis as a consequence of rises in gonadotropin levels at the mid-cycle. The increase of cyclic adenosine 3',5'-monophosphate (cAMP) and the activation of protein kinase A (PKA), protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) in cumulus cells are required for gonadotropins-induced meiotic resumption of oocytes. The various actions of cAMP activated by follicle-stimulating hormone (FSH) and luteinizing hormone (LH) also include meiosis activating sterol (MAS), gonadal steroid hormones and epidermal growth factor (EGF) network during meiotic resumption. Another second messenger guanosine 3',5'-cyclic monophosphate (cGMP) induced by nitric oxide (NO) or atrial natriuretic peptide (ANP) also mediates gonadotropins-controlled mammalian oocyte meiotic resumption. The different actions of FSH and LH on meiotic resumption are discussed. We hope to provide a framework to understand how the initial signals generated by gonadotropins-stimulation control the expression of genes required for meiotic resumption.
 ...
PMID:Gonadotropin-controlled mammal oocyte meiotic resumption. 1712 99

We have previously reported that angiotensin II (ANG II) treatment of A10 vascular smooth muscle cells (VSMCs) increased inhibitory G proteins (G(i) protein) expression and associated adenylyl cyclase signaling which was attributed to the enhanced MAP kinase activity. Since ANG II has been shown to increase oxidative stress, we investigated the role of oxidative stress in ANG II-induced enhanced expression of G(i)alpha proteins and examined the effects of antioxidants on ANG II-induced enhanced expression of G(i)alpha proteins and associated adenylyl cyclase signaling in A10 VSMCs. ANG II treatment of A10 VSMCs enhanced the production of O(2)(-) and the expression of Nox4 and P47(phox), different subunits of NADPH oxidase, which were attenuated toward control levels by diphenyleneiodonium (DPI). In addition, ANG II augmented the expression of G(i)alpha-2 and G(i)alpha-3 proteins in a concentration- and time-dependent manner; the maximal increase in the expression of G(i)alpha was observed at 1 to 2 h and at 0.1-1.0 microM. The enhanced expression of G(i)alpha-2 and G(i)alpha-3 proteins was restored to control levels by antioxidants such as N-acetyl-L-cysteine, alpha-tocopherol, DPI, and apocynin. In addition, ANG II also enhanced the ERK1/2 phosphorylation that was restored to control levels by DPI. Furthermore, the inhibition of forskolin-stimulated adenylyl cyclase activity by low concentrations of 5'-O-(3-triotriphosphate) (receptor-independent G(i) functions) and ANG II-, des(Glu(18),Ser(19),Glu(20),Leu(21),Gly(22))atrial natriuretic peptide(4-23)-NH(2) (natriuretic peptide receptor-C agonist), and oxotremorine-mediated inhibitions of adenylyl cyclase (receptor-dependent functions) that were augmented in ANG II-treated VSMCs was also restored to control levels by antioxidant treatments. In addition, G(s)alpha-mediated diminished stimulation of adenylyl cyclase by stimulatory hormones in ANG II-treated cells was also restored to control levels by DPI. These results suggest that ANG II-induced enhanced levels of G(i)alpha proteins and associated functions in VSMCs may be attributed to the ANG II-induced enhanced oxidative stress, which exerts its effects through mitogen-activated protein kinase signaling pathway.
 ...
PMID:Role of oxidative stress in angiotensin II-induced enhanced expression of Gi(alpha) proteins and adenylyl cyclase signaling in A10 vascular smooth muscle cells. 1715 44

[Arg8]-vasopressin (AVP) is an essential hormone for maintaining osmotic homeostasis and is known to be a potent vasoconstrictor that regulates the cardiovascular system. In the present study, cardiomyocytes were isolated from neonatal mice and used to investigate the effects of AVP on cardiac hypertrophy. Reverse transcription polymerase chain reaction (RT-PCR) analysis revealed that vasopressin V1A receptor mRNA, but not V1B or V2 receptor mRNA, was expressed in primary cultured neonatal mouse cardiomyocytes. By exposing the cultured neonatal cardiomyocytes to AVP for 24 h, cell surface areas were significantly increased, suggesting that AVP could induce cardiomyocyte growth. We then investigated the expression level of the atrial natriuretic peptide (ANP), which is a marker of cardiac hypertrophy. Stimulation with AVP increased the expression of cardiomyocyte ANP mRNA in a dose- and time-dependent manner. Immunocytochemical studies showed that stimulation with AVP significantly increased the expression of the ANP protein as well. Furthermore, AVP administration activated extracellular signal-regulated kinase (ERK)1/2 in cardiomyocytes. The effects of AVP on these parameters were significantly inhibited by a selective vasopressin V1A receptor antagonist, OPC-21268, and were not observed in cardiomyocytes from mice lacking the vasopressin V1A receptor. In vivo cardiac hypertrophy in response to pressure overload was attenuated in vasopressin V1A receptor-deficient (V1AR-KO) mice. Taken together, our data suggest that AVP promotes cardiomyocyte hypertrophy via the vasopressin V1A receptor, which is in part regulated by the pathway of ERK1/2 signaling.
 ...
PMID:Vasopressin promotes cardiomyocyte hypertrophy via the vasopressin V1A receptor in neonatal mice. 1727 6

Mitofusin-2 (Mfn2) suppresses smooth muscle cell proliferation through inhibition of the Ras-extracellular signal-regulated kinases (ERK1/2) pathway. Since the ERK1/2 pathway is implicated in mediating hypertrophic signaling, we studied the changes in Mfn2 in cardiac hypertrophy using in vitro and in vivo models. Phenylephrine was used to induce hypertrophy in neonatal rat ventricular myocytes (NRVMs). In vivo hypertrophy models included spontaneously hypertensive rats (SHR), pressure-overload hypertrophy by transverse aortic constriction (TAC), hypertrophy of non-infarcted myocardium following myocardial infarction (MI), and cardiomyopathy due to cardiac-restricted overexpression of beta(2)-adrenergic receptors (beta(2)-TG). We determined hypertrophic parameters and analysed expression of atrial natriuretic peptide (ANP) and Mfn2 by real-time PCR. Phosphorylated-ERK1/2 (phospho-ERK) was measured by Western blot. Mfn2 was downregulated in phenylephrine treated NRCMs (by approximately 40%), hypertrophied hearts from SHR (by approximately 80%), mice with TAC (at 1 and 3 weeks, by approximately 50%), and beta(2)-TG mice (by approximately 20%). However, Mfn2 was not downregulated in hypertrophied hearts with 15 weeks of TAC, nor in hypertrophied non-infarcted myocardium following MI. phospho-ERK1/2 was increased in hypertrophied myocardium at 1 week post-TAC, but not in non-infarcted myocardium after MI, indicating that downregulated Mfn2 may be accompanied by an increase of phospho-ERK1/2. This study shows, for the first time, downregulated Mfn2 expression in hypertrophied hearts, which depends on the etiology and time course of hypertrophy. Further study is required to examine the causal relationship between Mfn2 and cardiac hypertrophy.
 ...
PMID:Down-regulation of mitofusin-2 expression in cardiac hypertrophy in vitro and in vivo. 1749 11

Protein phosphatase 5 (PP5) is a unique member of the PPP family of serine/threonine phosphatases based on the presence of tetratricopeptide repeat (TPR) domains within its structure. Since its discovery, PP5 has been implicated in wide ranging cellular processes, including MAPK-mediated growth and differentiation, cell cycle arrest and DNA damage repair via the p53 and ATM/ATR pathways, regulation of ion channels via the membrane receptor for atrial natriuretic peptide, the cellular heat shock response as mediated by heat shock transcription factor, and steroid receptor signaling, especially glucocorticoid receptor (GR). Given this diversity of effects, the recent development of viable PP5-deficient mice was surprising and suggests that PP5 is a modulatory, rather than essential, factor in phosphorylation pathways. Here, we review the signaling involvement of PP5 in light of new findings and relate these activities to the structural features of the protein.
 ...
PMID:Protein phosphatase 5. 1795 Oct 98

We previously showed that S-nitroso-N-acetylpenicillamine, a nitric oxide donor, decreased the levels and functions of G(i)alpha proteins by formation of peroxynitrite (ONOO(-)) in vascular smooth muscle cells (VSMC). The present studies were undertaken to investigate whether ONOO(-) can modulate the expression of G(i)alpha protein and associated adenylyl cyclase signaling in VSMC. Treatment of A-10 and aortic VSMC with ONOO(-) for 24 h decreased the expression of G(i)alpha-2 and G(i)alpha-3, but not G(s)alpha, protein in a concentration-dependent manner; expression was restored toward control levels by (111)Mn-tetralis(benzoic acid porphyrin) and uric acid, but not by 1H[1,2,4]oxadiazole[4,3-a]quinoxaline-1-one (ODQ) and KT-5823. cGMP levels were increased by approximately 50% and 150% by 0.1 and 0.5 mM ONOO(-), respectively, and attenuated toward control levels by ODQ. In addition, 0.5 mM ONOO(-) attenuated the inhibition of adenylyl cyclase by ANG II and C-type atrial natriuretic peptide (C-ANP(4-23)), as well as the inhibition of forskolin-stimulated adenylyl cyclase activity by GTPgammaS, whereas, the G(s)-mediated stimulations were augmented. In addition, 0.5 mM ONOO(-) decreased phosphorylation of ERK1/2 and p38 MAP kinase and enhanced JNK phosphorylation but did not affect AKT1/3 phosphorylation. These results suggest that ONOO(-) decreased the expression of G(i) proteins and associated functions in VSMC through a cGMP-independent mechanism and may involve the MAP kinase signaling pathway.
 ...
PMID:Peroxynitrite inhibits the expression of G(i)alpha protein and adenylyl cyclase signaling in vascular smooth muscle cells. 1805 27

This study was designed to determine the effect of all-trans retinoic acid (RA) on the development of cardiac remodeling in a pressure overload rat model. Male Sprague-Dawley rats were subjected to sham operation and the aortic constriction procedure. A subgroup of sham control and aortic constricted rats were treated with RA for 5 mo after surgery. Pressure-overloaded rats showed significantly increased interstitial and perivascular fibrosis, heart weight-to-body weight ratio, and gene expression of atrial natriuretic peptide and brain natriuretic peptide. Echocardiographic analysis showed that pressure overload induced systolic and diastolic dysfunction, as evidenced by decreased fractional shortening, ejection fraction, stroke volume, and increased E-to-E(a) ratio and isovolumic relaxation time. RA treatment prevented the above changes in cardiac structure and function and hypertrophic gene expression in pressure-overloaded rats. RA restored the ratio of Bcl-2 to Bax, inhibited cleavage of caspase-3 and -9, and prevented the decreases in the levels of SOD-1 and SOD-2. Pressure overload-induced phosphorylation of ERK1/2, JNK, and p38 was inhibited by RA, via upregulation of mitogen-activated protein kinase phosphatase (MKP)-1 and MKP-2. The pressure overload-induced production of angiotensin II was inhibited by RA via upregulation of expression of angiotensin-converting enzyme (ACE)2 and through inhibition of the expression of cardiac and renal renin, angiotensinogen, ACE, and angiotensin type 1 receptor. Similar results were observed in cultured neonatal cardiomyocytes in response to static stretch. These results demonstrate that RA has a significant inhibitory effect on pressure overload-induced cardiac remodeling, through inhibition of the expression of renin-angiotensin system components.
 ...
PMID:All-trans retinoic acid prevents development of cardiac remodeling in aortic banded rats by inhibiting the renin-angiotensin system. 1817 13


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>