Biomedical subjects

Y Zou

Publications and source records attributed to Y Zou.

At least 145 records · Page 8Linked to original sources

PubMed1998

Cell type-specific angiotensin II-evoked signal transduction pathways: critical roles of Gbetagamma subunit, Src family, and Ras in cardiac fibroblasts.

Angiotensin II (Ang II) induces hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts. To determine the molecular mechanism by which Ang II displayed different effects on cardiac myocytes and fibroblasts, we examined signal transduction pathways leading to activation of extracellular signal-regulated kinases (ERKs). Ang II-induced ERK activation was abolished by pretreatment with pertussis toxin and by overexpression of the Gbetagamma subunit-binding domain of the beta-adrenergic receptor kinase 1 in cardiac fibroblasts but not in cardiac myocytes. Inhibition of protein kinase C strongly inhibited activation of ERKs by Ang II in cardiac myocytes, whereas inhibitors of tyrosine kinases but not of protein kinase C abolished Ang II-induced ERK activation in cardiac fibroblasts. Overexpression of C-terminal Src kinase (Csk), which inactivates Src family tyrosine kinases, suppressed the activation of transfected ERK in cardiac fibroblasts. Ang II rapidly induced phosphorylation of Shc and association of Shc with Grb2. Cotransfection of the dominant-negative mutant of Ras or Raf-1 kinase abolished Ang II-induced ERK activation in cardiac fibroblasts. Overexpression of Csk or the dominant-negative mutant of Ras had no effects on Ang II-induced ERK activation in cardiac myocytes. These findings suggest that Ang II-evoked signal transduction pathways differ among cell types. In cardiac fibroblasts, Ang II activates ERKs through a pathway including the Gbetagamma subunit of Gi protein, tyrosine kinases including Src family tyrosine kinases, Shc, Grb2, Ras, and Raf-1 kinase, whereas Gq and protein kinase C are important in cardiac myocytes.

Angiotensin II↗

PubMed1998

Mouse model of venous bypass graft arteriosclerosis.

Saphenous vein grafts are widely used for treatment of severe atherosclerosis via aortocoronary bypass surgery, a procedure often complicated by later occlusion of the graft vessel. Because the molecular mechanisms of this process remain largely unknown, quantitative models of venous bypass graft arteriosclerosis in transgenic mice could be useful to study this process at the genetic level. We describe herein a new model of vein grafts in the mouse that allows us to take advantage of transgenic, knockout, or mutant animals. Autologous or isogeneic vessels of the external jugular or vena cava veins were end-to-end grafted into carotid arteries of C57BL/6J mice. Vessel wall thickening was observed as early as 1 week after surgery and progressed to 4-, 10-, 15-, and 18-fold original thickness in grafted veins at age 2, 4, 8, and 16 weeks, respectively. The lumen of grafted veins was significantly narrowed because of neointima hyperplasia. Histological and immunohistochemical analyses revealed three lesion processes: marked loss of smooth muscle cells in vein segments 1 and 2 weeks after grafting, massive infiltration of mononuclear cells (CD11b/18+) in the vessel wall between 2 and 4 weeks, and a significant proliferation of vascular smooth muscle cells (alpha-actin+) to constitute neointimal lesions between 4 and 16 weeks. Similar vein graft lesions were obtained when external jugular veins or vena cava were isografted into carotid arteries of C57BL/6J mice. Moreover, no significant intima hyperplasia in vein-to-vein isografts was found, although there was leukocyte infiltration in the vessel wall. Thus, this model, which reproduces many of the features of human vein graft arteriosclerosis, should prove useful for our understanding of the mechanism of vein graft disease and to evaluate the effects of drugs and gene therapy on vascular diseases.

Anastomosis, Surgical↗

PubMed1998

Abundance of platelet-derived growth factors (PDGFs), PDGF receptors and activation of mitogen-activated protein kinases in brain decline with age.

Platelet-derived growth factors (PDGFs) specifically bind to PDGF receptors (PDGFRs), resulting in their activation via autophosphorylation and subsequent triggering of a cascade of phosphorylation events that include mitogen-activated protein (MAP) kinases. Most of our knowledge concerning MAP kinase activation comes from studies of cultured cells in vitro, and little is known about their activation in vivo. In the present study, we determined PDGF and PDGFR levels and MAP kinase activities, including extracellular signal-regulated protein kinases (ERK) and c-Jun NH2-terminal protein kinases (JNK) or stress-activated protein kinases (SAPK) in brain of young and older mice. Both PDGF and PDGFR proteins were most abundant in protein extracts from brain (cerebral cortex) among tissues of heart, liver, spleen, lung and kidney, as determined by Western blot analysis. PDGFR proteins in brain differed significantly between young (1 or 8 weeks) and older (14 months) mice and PDGFR phosphorylation was seen in all age groups examined by a specific antibody against phosphotyrosine. The highest activity ERK2 was also observed in brain tissues, and this activity declined with age, although ERK1 and ERK2 protein levels were not significantly altered during development and aging. Furthermore, the activity and amount of JNK/SAPK proteins were the most abundant in brain tissues and did not change with age. Thus, our findings demonstrate that the highest levels of PDGFs and PDGFRs existed in brain, and constitutive activation of MAP kinases declined with age, suggesting that signal pathways mediated by PDGF-MAP kinase cascades are important components in coordinating growth and differentiation of neurone and glial cells during development and aging.

Aging↗

PubMed1998

Detection and diagnosis of delirium in the elderly: psychiatrist diagnosis, confusion assessment method, or consensus diagnosis?

The clinical diagnosis of delirium has traditionally been based on an assessment by one or more physicians. Because of the transient, ubiquitous, and fluctuating nature of the symptoms of delirium, however, this approach may be flawed. Therefore, we decided to compare diagnosis based on one assessment by a psychiatrist, diagnosis by a nurse clinician (using the Confusion Assessment Method [CAM] and multiple observation points), and diagnosis by consensus. The study subjects were 87 patients aged 65 and over who were admitted consecutively from the emergency department to the medical wards, and who scored 3 or more on the Short Portable Mental Status Questionnaire. All subjects were assessed independently by one of three psychiatrists (a chart review and clinical examination) and a nurse clinician (using the CAM and multiple observation points). A consensus conference, attended by the three psychiatrists and the nurse clinician, used all available information to reach a consensus diagnosis. Compared to the consensus diagnosis, the clinical diagnosis by a psychiatrist had a sensitivity of .73 (95% confidence interval [CI]: .61-.85), a specificity of .93 (95% CI: .79-1.0), and an agreement kappa coefficient of .58 (95% CI: .41-.74). The nurse clinician diagnosis had a sensitivity of .89 (95% CI: .81-.97), a specificity of 1.00, and an agreement kappa coefficient of .86 (95% CI: .75-.97). These results suggest that one clinical assessment by a psychiatrist may not be the best method for detecting and diagnosing delirium in the elderly. A consensus diagnosis or diagnosis by a trained rater (using the CAM and multiple observation points) may be more sensitive approaches.

Aged↗

PubMed1998

Mapper: an intelligent restriction mapping tool.

MOTIVATION: To determine the most powerful artificial intelligence techniques for automated restriction mapping, and use them to create a powerful multiple-enzyme restriction mapping tool. RESULTS: The most effective search engine utilized model-driven exhaustive search and a form of binary logic pruning based on Pratt's separation theory. Additional experimentation led to the development of an input preprocessing module which significantly speeds up searches, and an output post-processing module which enables users to analyze large solution sets and reduce their apparent complexity. AVAILABILITY: An executable version of the resultant tool, Mapper, can be downloaded from our Web site (http://www.ai.eecs.uic.edu) by selecting the 'Software' option. CONTACT: nelson@eecs.uic.edu (http://www.ai.eecs.uic.edu/ñelson).

Algorithms↗

PubMed1998

Efficient inhibition of the development of cardiac remodeling by a long-acting calcium antagonist amlodipine.

The purpose of the present study was to examine the effects of a long-acting calcium antagonist, amlodipine, on the development of cardiac remodeling. Dihydropyridine calcium antagonists have been used widely for many years in the treatment of hypertension and angina pectoris. It has been reported, however, that a prototype of dihydropyridines, nifedipine, does not reduce mortality of patients with ischemic heart disease, possibly because of reflex stimulation of the sympathetic nervous system. A calcium antagonist, amlodipine, has been reported to have potential benefits by virtue of a gradual onset of action and a long duration of effects. Amlodipine (8 mg/kg per day, once a day) or nifedipine (24 mg/kg per day, three times a day) was administered to spontaneously hypertensive 12-week-old rats for 12 weeks. Left ventricular wall thickness was measured by echocardiography, and relative amounts of myosin heavy chain isoforms were assessed by pyrophosphate gels. Expressions of "fetal type" genes and type 1 collagen gene were examined by Northern blot analysis. Amlodipine and nifedipine both markedly reduced systolic blood pressure. However, the decrease in systolic blood pressure caused by nifedipine continued for no more than 8 hours, whereas the blood pressure-lowering effect of amlodipine continued for more than 16 hours post dose. Amlodipine markedly reduced left ventricular wall thickness, whereas nifedipine only weakly attenuated an increase in the wall thickness. Amlodipine, but not nifedipine, prevented an increase in the relative amount of V3 myosin heavy chain isoform and suppressed an increase in mRNA levels of beta-myosin heavy chain, skeletal alpha-actin, and type 1 collagen. Unlike nifedipine, amlodipine effectively prevented cardiac remodeling secondary to high blood pressure at biochemical levels and morphological levels. These results suggest that a long-acting calcium antagonist is more effective than a short-acting one in preventing organ injury in hypertensive subjects.

Amlodipine↗

PubMed1998

Signal transduction in arteriosclerosis: mechanical stress-activated MAP kinases in vascular smooth muscle cells (review).

Vascular smooth muscle cell (SMC) proliferation is a key event in the development of (spontaneous) atherosclerosis, hypertension-related arteriosclerosis, angioplasty-induced restenosis and venous bypass graft arteriosclerosis. Many factors or environmental stimuli are believed to be responsible for SMC growth or hypertrophy in the vessel wall. How these environmental stimuli or signals applied onto the surface of SMCs are transduced into the cell nucleus resulting in quantitative and qualitative changes in gene expression in SMCs of arterial walls is largely unknown. Mitogen-activated protein (MAP) kinases are rapidly activated in cells stimulated with various extracellular signals by dual phosphorylation of tyrosine and threonine residues. They are thought to play a pivotal role in transmitting transmembrane signals required for cell growth and differentiation. Recent studies have focused on the signalling events in vascular tissues in vivo and in cultured SMCs in vitro. It has been demonstrated that acute hypertension and angioplasty rapidly induced MAP kinase activation in the arterial wall. Kinase activation is followed by an increase in c-fos and c-jun gene expression and enhanced transcription factor AP-1 DNA-binding activity. A similar MAP kinase activation can be mimicked in in vitro cultured SMCs stimulated by either shear stress or cyclic strain stretch, suggesting direct effects of mechanical force. Interestingly, physical forces rapidly resulted in phosphorylation of platelet-derived growth factor (PDGF) receptor, an activated state, in cultured SMCs. Thus, mechanical stresses may directly perturb the cell surface or alter receptor conformation, thereby initiating signalling pathways usually used by growth factors. These findings have significantly enhanced our knowledge concerning the pathogenesis of arteriosclerosis and provide a basis for therapeutic intervention on vascular diseases.

Angioplasty↗

PubMed1998

[SurveilLance on filariasis after its basic elimination in Hunan Province].

AIM: To explore the fluctuation pattern of prevalence and to detect the residual infection in Hunan Province where filariasis had been basically eliminated since 1986. METHODS: Longitudinal surveillance and cross-sectional surveillance were extensively carried out by using parasitological, entomological and serological methods in areas previously endemic for filariasis. RESULTS: In 55 counties, cross-sectional surveillance on filariasis had been executed for 11-19 years. The results showed that microfilaria cases had not been found for 4 years, and filaria larvae had failed to be detected from mosquito vectors for 12 years. Serological surveillance in the population revealed that the mean positive rate of IFAT had dropped from 13.15% in 1987 to 1.06% in 1996, the latter rate being similar to that of the nonendemic area. 6 longitudinal surveillance spots in 5 counties (cities) had been observed for 10-17 years. Annual quantitative blood examination of 11 microfilariemia cases showed that 10 cases became negative in 1-10 years, and the remaining 1 case remained positive at the 14th year. A. sinensis were dissected with no filaria larvae found in 2 surveillance spots of malayan filariasis. Culex quinquefasciatus were dissected with filaria larvae found only in the first to third year, the natural infection rates were 0.38%-1.98% in 4 surveillance spots of bancroftian filariasis. CONCLUSION: Since the basic elimination of filariasis in Hunan Province in 1986, the number of residual microfilariemia cases decreased year after year, suggesting that the transmission of filariasis has been interrupted.

Animals↗

PubMed1998

[Subcloning and expression of coding region for cellulase binding domain of CBH I from P. janthinellum in E. coli].

The in vitro DNA manipulations, included the nested deletions, of cbh1 from P. janthinellum inserted into pUC18-181 were carried out. The two ends of fragments were modified into blunt ends and the fragments were self-ligated. Then, the encircled plasmids were transformed to E. coli JM109. Utilizing the characterization of CBD binding to crystalline cellulose, one catalytic domain deletion transformant producing active LacZ-CBD fusion protein was isolated from 24 transformants randomly picked from 400 transformants. The molecular weight of the LacZ-CBD fusion protein is 21 kD. The plasmid was designated pUC 18C. The LacZ-CBD fusion protein produced by JM109(pUC18C) was able to be purified by procedure of adsorption-desorption to cellulose. The pNPC activity of crude enzyme solution of JM109(pUC18C) induced by IPTG were zero, identified the JM109(pUC18C) has no CBHI activity.

Adsorption↗

PubMed1998

[Analysis of chemical components from Pheretima].

The total fat, total nitrogens, free amino acids, inorganic elements of Pheretima have been determined. It will provide scientific evidence for the establishment of quality standards of pheretima.

Amino Acids↗

PubMed1998

[Observation of the effect of pediatric secondary posterior-chamber intraocular lens implantation].

PURPOSE: To evaluate the effects of secondary posterior chamber lens implantation for aphakia in children. METHODS: Thirty-six consecutive pediatric aphakic eyes were retrospected. All eyes were secondarily implanted posterior-chamber lens using different operative techniques according to the condition of lens capsule remained after dissecting the posterior adhesion, forming extent space in posterior chamber. Follow-up ranged from 1 to 20 months. The effect of corrected visual acuity was observed. RESULTS: Postoperative nated visual acuity was equal or better than corrected visual acuity preoperatively in 22 eyes(61.1%). Postoperative corrected visual acuity was better than that before surgery in 32 eyes (88.8%) and was equal to that before surgery in 4 eyes(11.1%). CONCLUSIONS: Secondary posterior chamber IOLs implantation was an effective surgery for aphakic eyes in children, but attention should be paid to anti-inflammatory treatment and amblyopia treatment.

Amblyopia↗

PubMed1998

Effect of cataract surgery on ocular axial length elongation in young children.

PURPOSE: To evaluate the influence of cataract surgery on eyes of children between 1-5 years old. MATERIALS AND METHODS: Forty-seven cases of pediatric cataract, including 31 cases of bilateral congenital cataract and 16 cases of unilateral posttraumatic cataract, were retrospected. Of the 31 cases of congenital cataract, 19 cases (group 1) had undergone cataract extraction with intraocular lens (IOL) implantation, 12 (group 2) had undergone cataract extraction without IOL implantation. Each of them had their two eyes operated separately at an interval of 1 year or longer. Of the 16 cases of posttraumatic cataract, 6 (group 3) had undergone cataract extraction with IOL implantation and 10 (group 4) had undergone cataract extraction without IOL implantation. Mean age at the time of interested surgery was 2.9 years (range from 1.1 to 5.1 years). Ocular axial length of both eyes measured by A-scan ultrasonography before and after the surgery of the earlier operated eye in the congenital groups and the operated eye in the post-traumatic groups was recorded. The elongation of axial length of the earlier operated eye in the congenital groups and the operated eyes in the posttraumatic groups of each case were compared with that of the fellow eye statistically with paired t-test. RESULTS: The mean follow-up was 2.6 years (ranged from 1.0 to 6.4 years). In all the 4 groups, the elongation of axial length between the earlier operated eye and later operated eye in the congenital groups and between the operated and unoperated eyes in the posttraumatic groups of each case was not significantly different (p > 0.05). CONCLUSION: Cataract surgery, either extraction with or without IOL implantation, did not retard axial elongation in children above 1 year old.

Age Factors↗

PubMed1998

Evaluation of ocular safety: tirapazamine plus cisplatin in patients with metastatic melanomas.

Ninety-six patients with metastatic melanoma treated with two consecutive tirapazamine-cisplatin combination chemotherapy regimens were followed for signs of therapy-related ocular toxicity. Baseline and follow-up data were obtained such that each patient acted as his own control. A battery of vision-related tests was performed. These included: best corrected visual acuity, color vision, retinal fundus examination and electro-oculograms (EOG). A brief health-related quality of vision test was administered at each follow-up visit to detect and evaluate self-perceived changes in visual status. In the first study, 48 patients received i.v. tirapazamine over 2 h at 260 mg/m2 (group 1) while in the second study 48 patients (group 2) received i.v. tirapazamine at 390 mg/m2. Visual system assessment was conducted at three timepoints: first at baseline, then at 6 weeks post-baseline, i.e. after two courses of chemotherapy and visit two upon discontinuation of therapy. There was no difference in visual acuity between group 1 and group 2 at baseline, follow-up 1 or at follow-up 2. Grouped data indicate that visual acuity was not affected by either dosage of chemotherapy. Group 1 at baseline found 15% below the normal EOG cutoff point, increasing to 23% at follow-up 1 and increasing at follow-up visit 2 to 33%. Group 2 demonstrated the same EOG findings, but the results were more magnified: baseline, 24%; follow-up 1, 44%; and follow-up 2, 44%. After eliminating those with abnormal color vision baselines, 21% (nine of 42) group 1 patients demonstrated abnormal color vision total error scores at follow-up 1 and 16.7% (four of 24) at follow-up 2. Few individuals showed changes in the higher dosage group. With the exception of one person in each dosage group, all changes were along the blue-yellow (tritan) axis, which is associated with acquired color defects. Of 96 patients examined, proven fundus changes were found in only four subjects. These fundus findings included retinal hemorrhages, retinal nerve fiber layer infarcts (cotton wool spots) and small retinal pigment epithelium detachments. There was no systematic statistical significant difference among the various measures of visual system outcome between groups or test times. Data from all tests for individual patients in both groups reveals a sporadic distribution of changes in visual system tests. If toxicity were pronounced, one would expect consistency in the findings and all or most of the assessment tests would be abnormal for a particular patient. However, patients who were abnormal on one measure of acuity were not necessarily abnormal on the other measures.

Adult↗

PubMed1997

A precise interchromosomal reciprocal exchange between hot spots for cleavable complex formation by topoisomerase II in amsacrine-treated Chinese hamster ovary cells.

Among the aprt mutations induced in confluence-arrested Chinese hamster ovary D422 cells by the topoisomerase II poison amsacrine, there was a reciprocal exchange between the aprt gene and an unrelated sequence, accompanied by a chromosomal translocation at the aprt locus. The breakpoints in both parental sequences were hot spots for amsacrine-stimulated DNA cleavage in vitro, and the novel junctions formed were precisely as expected for a mechanism involving reciprocal exchange of topoisomerase II subunits followed by resealing of the breaks and correction of mismatches in the cohesive ends. The results are consistent with a role for direct subunit exchange in the production of chromosomal translocations by topoisomerase poisons, although more complex models involving double-strand breakage and repair could produce reciprocal exchanges of similar specificity.

Adenine Phosphoribosyltransferase↗

PubMed1997

Highly conservative reciprocal translocations formed by apparent joining of exchanged DNA double-strand break ends.

Chromosomal translocations induced by ionizing radiation and radiomimetic drugs are thought to arise by incorrect joining of DNA double-strand breaks. To dissect such misrepair events at a molecular level, large-scale, bleomycin-induced rearrangements in the aprt gene of Chinese hamster ovary D422 cells were mapped, the breakpoints were sequenced, and the original non-aprt parental sequences involved in each rearrangement were recovered from nonmutant cells. Of seven rearrangements characterized, six were reciprocal exchanges between aprt and unrelated sequences. Consistent with a mechanism involving joining of exchanged double-strand break ends, there was, in most cases, no homology between the two parental sequences, no overlap in sequences retained at the two newly formed junctions, and little or no loss of parental sequences (usually </=2 bp) at the breakpoints. The breakpoints were strongly correlated (P < 0.0001) with expected sites of bleomycin-induced, double-strand breaks. Fluorescence in situ hybridization indicated that, in six of the mutants, the rearrangement was accompanied by a chromosomal translocation at the aprt locus, because upstream and downstream flanking sequences were detected on separate chromosomes. The results suggest that repair of free radical-mediated, double-strand breaks in confluence-arrested cells is effected by a conservative, homology-independent, end-joining pathway that does not involve single-strand intermediate and that misjoining of exchanged ends by this pathway can directly result in chromosomal translocations.

Adenine Phosphoribosyltransferase↗

PubMed1997

Oxidative stress activates extracellular signal-regulated kinases through Src and Ras in cultured cardiac myocytes of neonatal rats.

A growing body of evidence has suggested that oxidative stress causes cardiac injuries during ischemia/reperfusion. Extracellular signal-regulated kinases (ERKs) have been reported to play pivotal roles in many aspects of cell functions and to be activated by oxidative stress in some types of cells. In this study, we examined oxidative stress-evoked signal transduction pathways leading to activation of ERKs in cultured cardiomyocytes of neonatal rats, and determined their role in oxidative stress-induced cardiomyocyte injuries. ERKs were transiently and concentration-dependently activated by hydrogen peroxide (H2O2) in cardiac myocytes. A specific tyrosine kinase inhibitor, genistein, suppressed H2O2-induced ERK activation, while inhibitors of protein kinase A and C or Ca2+ chelators had no effects on the activation. When CSK, a negative regulator of Src family tyrosine kinases, or dominant-negative mutant of Ras or of Raf-1 kinase was overexpressed, activation of transfected ERK2 by H2O2 was abolished. The treatment with H2O2 increased the number of cells stained positive by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, and induced formation of DNA ladder and activation of CPP32, suggesting that H2O2 induced apoptosis of cardiac myocytes. When H2O2-induced activation of ERKs was selectively inhibited by PD98059, the number of cardiac myocytes which showed apoptotic death was increased. These results suggest that Src family tyrosine kinases, Ras and Raf-1 are critical for ERK activation by hydroxyl radicals and that activation of ERKs may play an important role in protecting cardiac myocytes from apoptotic death following oxidative stress.

Animals↗

PubMed1997

Annamycin circumvents resistance mediated by the multidrug resistance-associated protein (MRP) in breast MCF-7 and small-cell lung UMCC-1 cancer cell lines selected for resistance to etoposide.

Annamycin (Ann) is a highly lipophilic anthracycline antibiotic that has been shown to circumvent MDR-1 both in vitro and in vivo. A liposomal formulation of Ann is currently in phase I clinical trials. The multidrug resistance-associated protein (MRP) has been found to be over-expressed in some human leukemias at relapse and to be a poor prognostic factor in neuroblastoma. We studied the in vitro cytotoxicity and the cellular uptake and efflux of Ann and doxorubicin (Dox) in 2 pairs of human cell lines, breast carcinoma MCF7 and small-cell lung cancer UMCC-1, and their MRP-expressing counterparts, MCF-7/VP and UMCC-1/VP. Resistance indexes were 1.1 and 1.4 for Ann vs. 6.9 and 11.6 for Dox. Ann cellular accumulation was 3- to 5-fold higher than that of Dox in both sensitive and resistant cells. No changes in drug efflux between sensitive and resistant cells were observed in the case of Ann, while Dox efflux at 1 hr was 20-25% higher in resistant than in sensitive cells. By confocal microscopy, the subcellular distribution of Ann was identical in sensitive and resistant cells, localizing mostly in the perinuclear structures, while that of Dox was exclusively nuclear in sensitive cells and nuclear and in the cell membrane in resistant cells. There was a good correlation between the extent of DNA breaks induced by each drug in the different cell lines and cytotoxic effect. Our results indicate that Ann may be effective in the treatment of malignancies in which MRP is a relevant mechanism of clinical resistance.

ATP-Binding Cassette Transporters↗

PubMed1997

Norepinephrine induces the raf-1 kinase/mitogen-activated protein kinase cascade through both alpha 1- and beta-adrenoceptors.

BACKGROUND: Although norepinephrine induces cardiac hypertrophy by activating protein kinase A and C through beta- and alpha 1-adrenoceptors, respectively, protein kinase A has been reported to inhibit cell growth in many other cell types. METHODS AND RESULTS: To elucidate the molecular mechanism of norepinephrine-induced hypertrophic responses, we examined the effects of protein kinase A and protein kinase C on the activities of raf-1 kinase and mitogen-activated protein (MAP) kinases and on protein synthesis rates using cultured cardiomyocytes of neonatal rats. Norepinephrine-induced activation of MAP kinases was partially inhibited by either an alpha 1-adrenoceptor blocker (prazosin) or a beta-adrenoceptor blocker (propranolol) and was completely abolished by both blockers. Both a beta-adrenoceptor agonist, isoproterenol, and an alpha 1-adrenoceptor agonist, phenylephrine, increased the activities of raf-1 kinase and MAP kinases and phenylalanine incorporation into proteins. Furthermore, isoproterenol and phenylephrine synergistically activated these kinases and protein synthesis. Similar synergistic activation of MAP kinases was observed when other protein kinase A-activating agents such as forskolin, dibutyryl cAMP, and isobutyl-methylxanthine were used with a protein kinase C-activating agent at the same time. Chelation of extracellular Ca2+ completely abolished isoproterenol- and phenylephrine-evoked MAP kinase activation. CONCLUSIONS: Norepinephrine activates the raf-1 kinase/MAP kinase cascade through both alpha 1- and beta-adrenergic stimulation, and signaling pathways from the two receptors synergistically induce cardiomyocyte hypertrophy.

1-Methyl-3-isobutylxanthine↗