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K M Baker

Publications and source records attributed to K M Baker.

At least 19 recordsLinked to original sources
PubMed2001

Role of transglutaminase II in retinoic acid-induced activation of RhoA-associated kinase-2.

Transamidation is a post-translational modification of proteins mediated by tissue transglutaminase II (TGase), a GTP-binding protein, participating in signal transduction pathways as a non-conventional G-protein. Retinoic acid (RA), which is known to have a role in cell differentiation, is a potent activator of TGASE: The activation of TGase results in increased transamidation of RhoA, which is inhibited by monodansylcadaverine (MDC; an inhibitor of transglutaminase activity) and TGaseM (a TGase mutant lacking transglutaminase activity). Transamidated RhoA functions as a constitutively active G-protein, showing increased binding to its downstream target, RhoA-associated kinase-2 (ROCK-2). Upon binding to RhoA, ROCK-2 becomes autophosphorylated and demonstrates stimulated kinase activity. The RA-stimulated interaction between RhoA and ROCK-2 is blocked by MDC and TGaseM, indicating a role for transglutaminase activity in the interaction. Biochemical effects of TGase activation, coupled with the formation of stress fibers and focal adhesion complexes, are proposed to have a significant role in cell differentiation.

Cytoskeleton↗
PubMed2001

The effect of muscle damage on strength and fatigue deficits.

Many studies have reported prolonged force deficits after a bout of resistance training. However there is a dearth of information on the neuromuscular mechanisms underlying these deficits. This study examined whether an acute bout of resistance training had prolonged detrimental effects on muscle activation and excitation-contraction coupling. Two groups of 16 subjects each were tested before resistance exercise and at 1, 3, 5, and 7 days postexercise. A dvnamic group was tested for concentric and eccentric 1 repetition maximum and 3-methylhistidine (3-MH). An isometric group was tested for maximal voluntary contraction, muscle inactivation, relative fatigue, and evoked twitch properties. Both groups experienced similar increases in pain, limb circumference, and decreased range of motion between 1 and 3 days postexercise. Decrements occurred with eccentric strength, maximal voluntary contraction, muscle inactivation, relative fatigue, twitch amplitude, and increases in 3-MH. Although muscle damage-induced characteristics (pain, swelling, range of motion, 3-MH) were not correlated with neuromuscular impairments (muscle activation, force output), disruption of excitation-contraction coupling may have contributed to decrements in fatigue.

Adaptation, Physiological↗
PubMed2000

Regulation of angiotensinogen gene expression and protein in neonatal rat cardiac fibroblasts by glucocorticoid and beta-adrenergic stimulation.

We previously demonstrated the presence of components for a renin-angiotensin system in fibroblasts cultured from neonatal rat ventricles, the regulation of expression of which has not been studied. Since glucocorticoids and beta-adrenergic stimuli have been implicated in cardiac hypertrophy, and function as regulators of the circulating renin-angiotensin system, we examined the effects of dexamethasone and isoproterenol on angiotensinogen mRNA levels and protein secretion in cultured neonatal rat cardiac fibroblasts. Treatment of cardiac fibroblasts for 8 h with 10 micromol/l isoproterenol or 100 nmol/l dexamethasone increased angiotensinogen mRNA levels by 246 +/- 7% and 1406 +/- 207%, respectively. Over 24 h, dexamethasone and isoproterenol increased angiotensinogen secretion by 148 +/- 32% and 123 +/- 26%, respectively. Angiotensin II, which has been reported to be a positive regulator of angiotensinogen synthesis and secretion in liver, markedly attenuated the effects of dexamethasone and isoproterenol on angiotensinogen mRNA expression and secretion. In the presence of 1 micromol/l angiotensin II, the stimulation in angiotensinogen secretion observed with dexamethasone and isoproterenol was decreased by 62% and 76%, respectively. The negative feedback of angiotensin II on angiotensinogen expression was primarily mediated through the type one angiotensin II (AT1) receptor (IC50 = 0.30 +/- 0.02 nmol/l). In summary, results from this study demonstrate that angiotensinogen mRNA levels and protein secretion in cardiac fibroblasts are positively regulated by glucocorticoid and beta-adrenergic stimulation. In addition, angiotensinogen production by cardiac fibroblasts is under negative feedback control of angiotensin II.

Adrenergic beta-Agonists↗
PubMed2000

Cardiotrophin-1 increases angiotensinogen mRNA in rat cardiac myocytes through STAT3 : an autocrine loop for hypertrophy.

-Cardiotrophin-1, an interleukin-6-related cytokine, stimulates the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway and induces cardiac myocyte hypertrophy. In this study, we demonstrate that cardiotrophin-1 induces cardiac myocyte hypertrophy in part by upregulation of a local renin-angiotensin system through the JAK/STAT pathway. We found that cardiotrophin-1 increased angiotensinogen mRNA expression in cardiac myocytes via STAT3 activation. Tyrosine phosphorylation of STAT3 by cardiotrophin-1 treatment resulted in STAT3 homodimer binding to the St-domain in the angiotensinogen gene promoter, which lead to promoter activation in a transient transfection assay. Cardiotrophin-1-induced STAT3 tyrosine phosphorylation and binding to the St-domain were suppressed by AG490, a specific JAK2 inhibitor, which also attenuated cardiotrophin-1-stimulated angiotensinogen promoter activity. Cardiotrophin-1 did not activate the angiotensinogen gene promoter that contained a substitution mutation within the St-domain. Finally, losartan, an angiotensin II type 1 receptor antagonist, significantly attenuated cardiotrophin-1-induced hypertrophy of neonatal rat cardiac myocytes. Angiotensin II is known to induce cardiac myocyte hypertrophy by activating the G-protein-coupled angiotensin II type 1 receptor. Our results suggest that upregulation of angiotensinogen and angiotensin II production contribute to cardiotrophin-1-induced cardiac myocyte hypertrophy and emphasize an important interaction between G-protein-coupled and cytokine receptors.

Angiotensin Receptor Antagonists↗
PubMed1999

The cardiac renin-angiotensin system: conceptual, or a regulator of cardiac function?

Angiotensin II, the effector peptide of the renin-angiotensin system, regulates cellular growth in response to developmental, physiological, and pathological processes. The identification of renin-angiotensin system components and angiotensin II receptors in cardiac tissue suggests the existence of an autocrine/paracrine system that has effects independent of angiotensin II derived from the circulatory system. To be functional, a local renin-angiotensin system should produce sufficient amounts of the autocrine and/or paracrine factor to elicit biological responses, contain the final effector (angiotensin II receptor), and respond to humoral, neural, and/or mechanical stimuli. In this review, we discuss evidence for a functional cardiac renin-angiotensin system.

Angiotensin II↗
PubMed1999

Amplification of angiotensin II signaling in cardiac myocytes by adenovirus-mediated overexpression of the AT1 receptor.

Low levels of AT1 receptor can make studying the growth-related signal transduction events mediated by this angiotensin II receptor in cardiac myocytes technically difficult. The purpose of the present study was to establish whether an adenovirus expression system could be used to increase the number of plasma membrane AT1 receptors in neonatal rat ventricular myocytes, thereby amplifying the signaling pathways activated by this receptor. Cardiac myocytes infected with adenovirus expressing the AT1 receptor exhibited increased ligand binding. The overexpressed receptor appeared to function like the endogenous receptor, in regard to agonist-induced internalization, as well as coupling to MAPK activation and protein tyrosine phosphorylation events. In addition, adenovirus-mediated overexpression of the AT1 receptor resulted in the amplification of angiotensin II intracellular signaling. In conclusion, adenovirus-mediated overexpression of angiotensin II receptors appears to be a useful strategy for studying the signal transduction events activated by this hormone in cardiac myocytes and for unraveling the molecular means by which this receptor type couples to a hypertrophic pattern of growth and gene expression.

Adenoviridae↗
PubMed1999

Paracrine actions of cardiac fibroblasts on cardiomyocytes: implications for the cardiac renin-angiotensin system.

Conditioned medium of cardiac fibroblasts was found to induce protein synthesis and signal transduction events rapidly, and to increase angiotensinogen messenger RNA (mRNA) levels in neonatal rat ventricular myocytes. Within 4 hours, fibroblast-conditioned medium (FCM) stimulated protein synthesis in cardiac myocytes, independent of the contractile state, and induced marked increases within 24 hours in total protein content. Endothelin- released by cardiac fibroblasts was not responsible for the stimulation of protein synthesis. FCM rapidly activated signal transduction events in cardiac myocytes associated with hypertrophic stimuli, including: (1) increased tyrosine phosphorylation of several prominent protein bands; (2) mitogen-activated protein kinases (ERK 1 and ERK 2); and (3) protein kinase C. Finally, FCM caused an increase at 8 hours in angiotensinogen mRNA levels of cardiac myocytes, whereas no effect was observed on mRNA levels for renin or the type 1 angiotensin II receptor (AT1). Our results suggest that cardiac fibroblasts produce a factor that rapidly activates cardiac myocyte growth through a membrane receptor that couples to conventional signal transduction pathways.

Angiotensinogen↗
PubMed1999

Angiotensin II-stimulated induction of sis-inducing factor is mediated by pertussis toxin-insensitive G(q) proteins in cardiac myocytes.

The Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway is stimulated by angiotensin II (Ang II) via the type 1 receptor after acute pressure overload in the heart. The purpose of this study was to determine whether activation of the JAK-STAT pathway by Ang II is dependent on G proteins. Ang II (100 nmol/L for 120 minutes) caused formation of sis-inducing factor (SIF) complexes and tyrosine phosphorylation of STAT proteins in neonatal rat ventricular myocytes. The percentage of change in Ang II-stimulated SIF induction was not affected by pertussis toxin (PTX) or GP antagonist-2A, compounds that inhibit activation of G(i) and G(o) proteins. In contrast, GP antagonist-2A, a peptide that selectively inhibits activation of G(q) proteins, completely abolished Ang II-stimulated SIF induction and STAT3 tyrosine phosphorylation. Pretreatment of cardiac myocytes with U73122, an inhibitor of phosphatidylinositol-specific phospholipase C (PLC) activity, decreased Ang II-stimulated SIF induction and STAT3 tyrosine phosphorylation in a dose-dependent manner. Chelation of intracellular Ca(2+) with BAPTA-AM did not alter Ang II-stimulated SIF induction. In contrast, pretreatment of cardiac myocytes with Ro-31-8220, a potent and specific inhibitor of protein kinase C (PKC), decreased Ang II-stimulated SIF induction in a dose-dependent manner. Ang II-stimulated SIF induction was abolished in cardiac myocytes after downregulation of PKC by treatment with PMA. From these data, we conclude that Ang II-stimulated SIF induction and STAT3 tyrosine phosphorylation is mediated by PTX-insensitive G proteins through a G(q)-PLC-PKC-mediated pathway in neonatal rat ventricular myocytes.

Angiotensin II↗
PubMed1998

alpha-Thrombin inhibits signal transducers and activators of transcription 3 signaling by interleukin-6, leukemia inhibitory factor, and ciliary neurotrophic factor in CCL39 cells.

We recently demonstrated that, in rat aortic smooth muscle cells, alpha-thrombin stimulated Stat3/SIF-A (signal transducers and activators of transcription 3/sis-inducing factor-A) activity [G. J. Bhat et al. (1997) Hypertension 29(Pt. 2), 356-360]. In the present study, we observed that exposure of CCL39 cells (a Chinese hamster lung fibroblast cell line) to alpha-thrombin resulted in a time-dependent decrease in basal SIF-A activity. We hypothesized that the decrease in basal SIF-A was due to the initiation of an inhibitory pathway, following alpha-thrombin exposure. To test this hypothesis, we determined if alpha-thrombin would inhibit Stat3 and SIF-A activation by interleukin-6 (IL-6), leukemia inhibitory factor (LIF), and ciliary neurotrophic factor (CNTF). In support of this hypothesis, alpha-thrombin inhibited the Stat3/SIF-A response induced by all the above cytokines. The inhibition by alpha-thrombin was concentration dependent, was sensitive to hirudin, and was mimicked by the thrombin receptor agonist peptide. The inhibition did not require the activation of phorbol 12-myristate 13-acetate-sensitive isoforms of protein kinase C and was reversed by pretreatment with the mitogen-activated protein kinase kinase 1 (MAPKK1 or MEK1) inhibitor PD98059. Inhibitory cross talk between alpha-thrombin and IL-6 was also observed in MRC-5 cells, a fibroblast cell line derived from human lung tissue. Thus, we identify a novel alpha-thrombin inhibitory pathway which, acting through a MAPKK1-dependent mechanism, blocks IL-6-, LIF-, and CNTF-induced Stat3/SIF-A activation. This inhibitory cross talk may provide an important regulatory function to modulate gene transcription by these cytokines, during immune and inflammatory responses.

Animals↗
PubMed1998

Functional role for the angiotensin II receptor (AT1A) 3'-untranslated region in determining cellular responses to agonist: evidence for recognition by RNA binding proteins.

We demonstrate a functional role for the 3'-untranslated region (3'-UTR) of the angiotensin II (Ang II) receptor subtype AT1A mRNA in Chinese hamster ovary (CHO-K1) cells by stably transfecting the coding region of the receptor gene with or without the 845 bp 3'-UTR. Two cell lines expressing similar levels of cell-surface receptors (with 3'-UTR, Bmax=571 fmol/mg protein; without 3'-UTR, Bmax=663 fmol/mg protein) were used in the present study. Both cell lines expressed high-affinity receptors (with 3'-UTR, Kd=0.83 nM; without 3'-UTR, Kd=0.82 nM), and binding studies with 125I-labelled Ang II in the presence of GTP[S] demonstrated that both coupled to heterotrimeric G-proteins. Despite these similarities, significant differences were observed for receptor-mediated cell signalling pathways. In cells without the 3'-UTR, Ang II stimulated an increase in cAMP accumulation (11-fold above control) and in cells with the 3'-UTR no stimulation was observed, which was consistent with previous observations in most endogenous Ang II receptor (AT1)-expressing cells. Activation of cAMP by Ang II in cells without the 3'-UTR correlated with an inhibition of DNA synthesis, determined by [3H]thymidine incorporation. Ang II-mediated responses were blocked by EXP3174, a selective non-peptide receptor antagonist. We also observed differences in the transient profiles of intracellular calcium between cells with and without the 3'-UTR in response to Ang II. In cells with the 3'-UTR, a sustained level of intracellular calcium was observed after Ang II stimulation, whereas cells without the 3'-UTR displayed a full return to basal level within 50 s of Ang II treatment. Even though the expressed exogenous gene is under the control of a constitutively expressing promoter (cytomegalovirus promoter), Northern-blot analysis revealed a considerably greater accumulation of AT1A mRNA in cells without the 3'-UTR compared with cells with the 3'-UTR. Analysis of the decay rate of the AT1A mRNA in cells with and without the 3'-UTR revealed that the normally unstable AT1A receptor mRNA became highly stable by removing its 3'-UTR, identifying a role for the 3'-UTR in mRNA destabilization. Interestingly, both cells express similar levels of receptors at the cell surface, suggesting that the 3'-UTR is also involved in the efficient translation and/or translocation of the receptor protein to the plasma membrane. We hypothesized that these 3'-UTR-mediated functions of the receptor are regulated by RNA-binding proteins. To identify possible RNA-binding proteins for the AT1A 3'-UTR, cellular extracts were prepared from parental CHO-K1 cells and 3'-UTR-binding assays, electrophoretic mobility-shift assays and UV crosslinking studies were performed. A major cellular protein of 55 kDa was identified, which specifically interacted with the 3'-UTR. Our data suggest that the 3'-UTR of the AT1A can control specific receptor functions, perhaps via selective recognition of the 3'-UTR by RNA-binding proteins.

Angiotensin II↗
PubMed1998

Cross-talk between angiotensin II and interleukin-6-induced signaling through Stat3 transcription factor.

In cultured neonatal rat cardiac fibroblasts and CHO-K1 cells expressing angiotensin II (Ang II) type 1 receptors (AT1) (T3CHO/AT1A cell line), Ang II induced a delayed tyrosine phosphorylation of Stat3 (Signal Transducers and Activators of Transcription) with maximal activation at 2 h. This was in contrast to the rapid tyrosine phosphorylation (15-30 min) of Stat3 by the cytokine interleukin-6 (IL-6). Using T3CHO/AT1A cells, we tested the hypothesis that the delayed tyrosine phosphorylation of Stat3 by Ang II resulted from the induction of an inhibitory pathway (0-30 min) prior to activation (1-2 h). In support of this hypothesis, we observed that a short treatment of cells with Ang II transiently inhibited the IL-6-induced Stat3 tyrosine phosphorylation. The inhibitory effect of Ang II could be attenuated by exposing the cells to a specific inhibitor of MAP kinase kinase 1, PD98059. Such modulatory cross-talk between Ang II and IL-6 may have relevance in pathophysiological conditions such as cardiac hypertrophy, and in acute phase and inflammatory responses.

Angiotensin II↗
PubMed1998

Half-Fourier RARE MR cholangiopancreatography: experience in 300 subjects.

PURPOSE: To determine prospectively the clinical applications and diagnostic accuracy of half-Fourier rapid acquisition with relaxation enhancement (RARE) magnetic resonance (MR) cholangiopancreatography (MRCP) in a large patient population. MATERIALS AND METHODS: Breath-hold, heavily T2-weighted half-Fourier RARE MRCP was performed in 265 patients with suspected pancreaticobiliary disease and in 35 control patients without symptoms or signs referrable to the biliary tract or pancreatic duct. MRCP findings were correlated with those at direct cholangiography, pathologic examination, cross-sectional imaging, and clinical follow-up. RESULTS: Diagnostic MRCP examinations were obtained in 299 (99.7%) subjects. MRCP yielded an accuracy of 100% in determining the presence of pancreaticobiliary disease, the presence and level of biliary obstruction, and obstruction due to bile duct calculi. The accuracy of MRCP and MR imaging in determining the presence and level of malignant obstruction was 98.2%. MRCP obviated endoscopic retrograde cholangiopancreatography (ERCP) by excluding choledocholithiasis in patients with acute pancreatitis (n = 13) and nonspecific abdominal pain (n = 82). In patients with sclerosing cholangitis and acquired immunodeficiency syndrome cholangiopathy, MRCP depicted the biliary tract as clearly as did ERCP (n = 9). After failed ERCP, MRCP delineated the pancreaticobiliary tract and helped determine therapeutic options (n = 27). CONCLUSION: Half-Fourier RARE MRCP enables accurate evaluation of pancreaticobiliary disease and obviates ERCP in some patients.

Adolescent↗
PubMed1998

Phosphorylation of the angiotensin II (AT1A) receptor carboxyl terminus: a role in receptor endocytosis.

The molecular mechanism of angiotensin II type I receptor (AT1) endocytosis is obscure, although the identification of an important serine/threonine rich region (Thr332Lys333Met334Ser335Thr336Leu337 Ser338) within the carboxyl terminus of the AT1A receptor subtype suggests that phosphorylation may be involved. In this study, we examined the phosphorylation and internalization of full-length AT1A receptors and compared this to receptors with truncations and mutations of the carboxyl terminus. Epitope-tagged full-length AT1A receptors, when transiently transfected in Chinese hamster ovary (CHO)-K1 cells, displayed a basal level of phosphorylation that was significantly enhanced by angiotensin II (Ang II) stimulation. Phosphorylation of AT1A receptors was progressively reduced by serial truncation of the carboxyl terminus, and truncation to Lys325, which removed the last 34 amino acids, almost completely inhibited Ang II-stimulated 32P incorporation into the AT1A receptor. To investigate the correlation between receptor phosphorylation and endocytosis, an epitope-tagged mutant receptor was produced, in which the carboxyl-terminal residues, Thr332, Ser335, Thr336, and Ser338, previously identified as important for receptor internalization, were substituted with alanine. Compared with the wild-type receptor, this mutant displayed a clear reduction in Ang II-stimulated phosphorylation. Such a correlation was further strengthened by the novel observation that the Ang II peptide antagonist, Sar(1)Ile8-Ang II, which paradoxically causes internalization of wild-type AT1A receptors, also promoted their phosphorylation. In an attempt to directly relate phosphorylation of the carboxyl terminus to endocytosis, the internalization kinetics of wild-type AT1A receptors and receptors mutated within the Thr332-Ser338 region were compared. The four putative phosphorylation sites (Thr332, Ser335, Thr336, and Ser338) were substituted with either neutral [alanine (A)] or acidic amino acids [glutamic acid (E) and aspartic acid (D)], the former to prevent phosphorylation and the latter to reproduce the acidic charge created by phosphorylation. Wild-type AT1A receptors, expressed in Chinese hamster ovary cells, rapidly internalized after Ang II stimulation [t1/2 2.3 min; maximal level of internalization (Ymax) 78.2%], as did mutant receptors carrying single acidic substitutions (T332E, t1/2 2.7 min, Ymax 76.3%; S335D, t1/2 2.4 min, Ymax 76.7%; T336E, t1/2 2.5 min, Ymax 78.2%; S338D, t1/2 2.6 min, Ymax 78.4%). While acidic amino acid substitutions may simply be not as structurally disruptive as alanine mutations, we interpret the tolerance of a negative charge in this region as suggestive that phosphorylation may permit maximal internalization. Substitution of all four residues to alanine produced a receptor with markedly reduced internalization kinetics (T332A/S335A/T336A/S338A, t1/2 10.1 min, Ymax 47.9%), while endocytosis was significantly rescued in the corresponding quadruple acidic mutant (T332E/S335D/T336E/S338D, t1/2 6.4 min, Ymax 53.4%). Double mutation of S335 and T336 to alanine also diminished the rate and extent of endocytosis (S335A/T336A, 3.9 min, Ymax 69.3%), while the analogous double acidic mutant displayed wild type-like endocytotic parameters (S335D/T336E, t1/2 2.6 min, Ymax 77.5%). Based on the apparent rescue of internalization by acidic amino acid substitutions in a region that we have identified as a site of Ang II-induced phosphorylation, we conclude that maximal endocytosis of the AT1A receptor requires phosphorylation within this serine/threonine-rich segment of the carboxyl terminus.

Angiotensin II↗
PubMed1997

Long-term survival in typical thanatophoric dysplasia type 1.

Thanatophoric dysplasia (TD), a severe skeletal dysplasia, is virtually always lethal neonatally, although a few previous reports have documented survival up to 4.75 years. We present a patient with survival beyond age 9 years and summarize his growth, development and medical history. The common Arg248Cys mutation in the extracellular region of fibroblast growth factor receptor 3 (FGFR3) was identified, eliminating the possibility that his long-term survival is attributable to an atypical mutation. This patient (and at least one other TD long-term survivor) have a rare skin disorder, acanthosis nigricans, which also occurs in Crouzon syndrome when caused by a FGFR3 mutation. Therefore, any molecular model of the origin of acanthosis nigricans secondary to FGFR3 mutations must account for the association of diverse mutations and these cutaneous effects.

Acanthosis Nigricans↗
PubMed1997

The type I angiotensin II receptor couples to Stat1 and Stat3 activation through Jak2 kinase in neonatal rat cardiac myocytes.

The octapeptide, angiotensin II, has a modulatory role on cardiac cellular growth associated with hypertension and in compensatory remodeling following myocardial infarction. The molecular signal transduction pathways that participate in these and other cellular actions in response to angiotensin II are presently being elucidated. The signal transducers and activators of transcription (STAT) pathway directly links cytokine and growth factor receptors with transcriptional activity. We provide evidence that the G protein-linked, angiotensin II, AT1-receptor couples to activation of the STAT pathway in neonatal rat cardiac myocytes. Angiotensin II induces primarily sis-inducing factor (SIF) B and to a lesser extent SIF-C and SIF-A. The EC50 of this response was 40 nM and Stat1 and Stat3 proteins were identified as components of the SIF complexes. Stat1 and Stat3 were tyrosine phosphorylated five-fold and three-fold, respectively, over control levels following angiotensin II treatment of cardiac myocytes. Phosphorylation of Stat1 and Stat3 proteins was rapid (5 min) and sustained (60 min). Jak2 was also tyrosine phosphorylated eight-fold by angiotensin II treatment, and phosphorylated Stat1 and Stat3 proteins co-immunoprecipitated with activated Jak2 kinase. Selective inhibition of Jak2 kinase with AG-490 blocked formation of angiotensin II induced SIF complexes, suggesting that Jak2 kinase is required for cardiomyocyte SIF induction. In addition, Jak2, Stat1 and Stat3 proteins co-immunoprecipitated with the AT1-receptor. These are the first data to demonstrate coupling of a G-protein coupled receptor, AT1, to the JAK-STAT pathway in primary cultured cardiac myocytes and suggest that this pathway may be involved in transcriptional regulation by angiotensin II.

Angiotensin II↗
PubMed1997

Molecular mechanisms of angiotensin II in modulating cardiac function: intracardiac effects and signal transduction pathways.

Angiotensin II (Ang II), the effector peptide of the renin-angiotensin system (RAS), regulates volume and electrolyte homeostasis and is involved in cardiac and vascular cellular growth in humans and other species. This system, which has been conserved throughout evolution, plays an important role in cardiac and vascular pathology associated with hypertension, coronary heart disease, myocarditis and congestive heart failure. The traditional RAS is viewed as a system in which circulating Ang II is delivered to target organs and cells. However, in the past decade, a local RAS has been described in cardiac cells, providing evidence for autocrine and paracrine pathways by which biological actions of Ang II could be mediated. The critical actions of Ang II are mediated primarily through the AT1, G-protein (guanylyl nucleotide binding protein) coupled receptor. In addition to coupling to conventional G-protein signal transduction pathways, the AT1 receptor was recently shown to increase the tyrosine phosphorylation of several intracellular substrates, including the STAT (Signal Transducers and Activators of Transcription) family of novel transcription factors, in rat cardiac fibroblasts, myocytes and vascular smooth muscle cells, and AT1 receptor transfected CHO cells. It has been shown that Ang II stimulates the tyrosine phosphorylation and nuclear translocation of Stat1 (Stat 91) and Stat3 (Stat 92). Angiotensin II acting directly through the AT1 receptor, induces the formation of a complex of STAT proteins termed SIF (sis-inducing factor) which binds the DNA sequence, SIE (sis-inducing element) present in the promotor element of many genes. This provides evidence for a direct role of Ang II in mediating inflammatory and remodeling responses through the JAK-STAT pathway. Thus, it is likely that the JAK-STAT pathway has an important role in Ang II-mediated effects on gene transcription, cardiac and vascular cellular growth/development, and inflammatory responses.

Angiotensin II↗
PubMed1997

Angiotensin II stimulates rapid serine phosphorylation of transcription factor Stat3.

In rat neonatal cardiac fibroblasts and CHO-K1 cells expressing angiotensin type 1 receptors, angiotensin II (AII) rapidly caused a time dependent reduction in the SDS-polyacrylamide gel electrophoretic mobility of Stat3 (Signal Transducer and Activator of Transcription). This was concentration dependent and detected at a low/physiological concentration of AII (1 nM), with initial effect observed as early as 2 min; and maximal at 5 min. The rapid stimulation of Stat3 mobility retardation by AII, paralleled the rapid activation of MAP kinases (mitogen-activated protein kinases), and both were sensitive to the MAP kinase kinase 1 inhibitor, PD98059. Immunoprecipitation of Stat3 from [32P] labeled cells demonstrated a 4-fold increase in Stat3 phosphorylation in response to AII, and phosphoamino acid analysis indicated that phosphorylation occurred on serine residues. Angiotensin II-induced rapid phosphorylation of Stat3 was also sensitive to the MAP kinase kinase 1 inhibitor, PD98059. Treatment of immunoprecipitated Stat3 from AII-treated cells with protein phosphatase- PP-2A, reversed the AII-induced retardation of Stat3 mobility. These results demonstrate that AII rapidly induces Stat3 serine phosphorylation through a MAP kinase kinase 1 dependent pathway. Rapid stimulation of Stat3 serine phosphorylation by AII may have implications in the modulation of its transcriptional activity and gene expression.

Angiotensin I↗