Biomedical subjects

L Liu

Publications and source records attributed to L Liu.

At least 541 records · Page 30Linked to original sources

PubMed1999

Transgenic expression of human MGMT blocks the hypersensitivity of PMS2-deficient mice to low dose MNU thymic lymphomagenesis.

Mice deficient in the DNA mismatch repair (MMR) gene, PMS2, develop spontaneous thymic lymphomas and sarcomas. We have previously shown that PMS2(-/-) mice were hypersensitive to a single i.p. injection of 50 mg/kg of N-methyl-N-nitrosourea (MNU) for thymic lymphoma induction. We postulated that MNU sensitivity was due to formation of O(6)-methylguanine (O(6)-mG), which, if unrepaired by O(6)-alkylguanine DNA alkyltransferase (AGT), leads to apoptosis in MMR competent cells and O(6)-mG:T mismatches in MMR deficient cells. Tumor induction is less in MMR(+/+) mice because cells with residual DNA adducts die, whereas mutagenized cells survive in MMR(-/-) mice. Overexpression of AGT (encoded by the methylguanine DNA methyltransferase-MGMT-gene) is known to block MNU induced tumorigenesis in mice with functional MMR. To further determine the sensitivity of PMS2(-/-) mice to MNU and the protective effect of hAGT overexpression, a low dose of MNU (25 mg/kg) was studied in PMS2(-/-) mice and PMS2(-/-)/hMGMT(+) mice. No thymic lymphomas were found in MNU-treated PMS2(+/+) and PMS2(+/-) mice. At 1 year, 46% of the MNU-treated PMS2(-/-) mice developed thymic lymphoma, compared with an incidence of 25% in both untreated PMS2(-/-) mice and MNU treated PMS2(-/-)/hMGMT(+) mice. In addition, a significantly shorter latency in the onset of thymic lymphomas was seen in MNU-treated PMS2(-/-) mice. K-ras mutations were detected almost equally in the thymic lymphomas induced by MNU in both PMS2(-/-) and PMS2(-/-)/hMGMT(+) mice, but not in the spontaneous lymphomas. These data suggest that PMS(-/-) mice are hypersensitive to MNU, that there are different pathways responsible for spontaneous and MNU induced thymic lymphomas in PMS2(-/-) mice, and that overexpression of hMGMT protects the mice by blocking non-K-ras pathways.

Adenosine Triphosphatases↗

PubMed1999

The elevated ratio of interferon gamma-/interleukin-4-positive T cells found in synovial fluid and synovial membrane of rheumatoid arthritis patients can be changed by interleukin-4 but not by interleukin-10 or transforming growth factor beta.

OBJECTIVES: To quantify the T-helper type (Th) 1 cytokine interferon gamma (IFN-gamma)-positive and the Th2 cytokine interleukin (IL)-4-positive cells in synovial fluid (SF) and synovial membrane (SM) at the single-cell level in rheumatoid arthritis (RA) in comparison to reactive arthritis (ReA), and to manipulate the cytokine pattern of RA patients in vitro. METHODS: Eighteen patients with RA and 17 with ReA were studied. For intracellular staining of cytokines, SF mononuclear cells (MNC) from seven patients with RA, in comparison to eight patients with ReA, were triple stained with anti-IFN-gamma, IL-4 and anti-CD4 or anti-CD8 monoclonal antibodies (mAb) and analysed by flow cytometry. Furthermore, in 13 patients with RA, immunohistology of SM was performed and compared with seven ReA patients. In addition, in six of the RA patients, synovial T cells were grown over 3 weeks in the presence of various cytokines and intracellular cytokine staining analysed by flow cytometry weekly. RESULTS: In SF, the mean percentage of IFN-gamma+/CD4+ T cells in RA was almost 4-fold higher than the number of IL-4+/CD4+ T cells (11.3+/-5 vs 3.02+/-1.04; P=0.0012), while the ratio of IFN-gamma/IL-4+ CD4+ T cells was only 1.59 in ReA (P=0.047 for the ratio difference). A similar result was obtained for SM: the ratio of IFN-gamma/IL-4+ cells in RA was 4.3 (P<0.0001 for the IFN-gamma/IL-4 difference), but only 1.2 for ReA (P=0.02 for the ratio difference). Of the CD3+ cells in SM, 2.8% were positive for IFN-gamma and 0.4% for IL-4 in three RA patients. A decrease in the number of IFN-gamma-positive SF T cells and an increase in the number of IL-4-positive SF T cells could be achieved in vitro through IL-4, but not by IL-10 or transforming growth factor beta. CONCLUSIONS: The Th1 pattern in the joint of RA patients demonstrated at the single-cell level may be important for the pathogenesis of RA and may provide a target for future immunotherapy. Our data suggest a therapeutic role for IL-4.

Adolescent↗

PubMed1999

Interplay of maturation-promoting factor and mitogen-activated protein kinase inactivation during metaphase-to-interphase transition of activated bovine oocytes.

The objective of the present study was to examine the activity changes in histone H1 kinase (also known as maturation-promoting factor [MPF]) and mitogen-activated protein kinase (MAPK) and their constituent proteins in in vitro-matured bovine oocytes after in vitro fertilization (IVF) or after parthenogenetic activation induced by calcium ionophore A23187 alone or by the ionophore followed by either 6-dimethylaminopurine (6-DMAP) or cycloheximide (CHX). Inactivation of both H1 kinase and MAPK occurred after both A23187+6-DMAP treatment and IVF; inactivation of H1 kinase preceded inactivation of MAPK. However, MAPK was inactivated much earlier in 6-DMAP-treated oocytes. Further analysis of constituent cell cycle proteins of these kinases by Western blot showed that A23187 alone could not induce changes in cdc2, cdc25, or ERK2 but induced reduction of cyclin B1. IVF and A23187+CHX induced similar changes: cyclin B1 was destroyed shortly after activation followed by accumulation of cyclin B1, phosphorylation of cdc2, and dephosphorylation of ERK2 at pronuclear formation 15 h after activation. No change in cdc25 was observed at this time. In contrast, A23187+6-DMAP treatment resulted in earlier phosphorylation of cdc2 and dephosphorylation of ERK2 at 4 h after treatment when the pronucleus formed. Moreover, accumulation of both cdc25 and cyclin B1 was detected at 15 h. Microinjection of ERK2 antibody into A23187-treated oocytes resulted in pronuclear formation. In conclusion, activation of bovine oocytes with 6-DMAP led to earlier inactivation of MAPK, while CHX induced inactivation of MAPK parallel to that following sperm-induced oocyte activation. Destruction of cyclin B is responsible for inactivation of MPF, while phosphorylation of cdc2 is likely responsible for maintaining its low activity. Inactivation of MAPK is closely associated with pronuclear development regardless of the activation protocol used.

Adenine↗

PubMed1999

Thiol oxidation-induced embryonic cell death in mice is prevented by the antioxidant dithiothreitol.

The oxidation of cellular sulfhydryl (SH) groups has been implicated in the induction of apoptosis in various types of cells and in the disturbance of the meiotic spindle of murine oocytes during aging. The objective of this study was to determine whether the SH-specific oxidant diamide could inhibit embryo development and induce cell death, and whether the antioxidant dithiothreitol (DTT) could counteract such effects. Exposure of mouse zygotes to diamide for 3 h at 25 or 50 microM (but not 12.5 microM) resulted in cell cycle arrest and cell death with evidence of apoptosis. At higher concentrations (100 or 200 microM), diamide induced necrosis as evidenced by propidium iodide-positive pronuclei within 24 h of treatment. Simultaneous addition of DTT at equimolar concentration prevented these effects. However, when DTT was added later, it was no longer protective. DTT also effectively protected against the thiol-oxidative damage caused by diamide in blastocysts. These results suggest that altering thiol-redox status in zygotes and blastocysts may result in cell cycle arrest, apoptosis, and/or cell death.

Animals↗

PubMed1999

Genotyping and functional analysis of a polymorphic (CCTTT)(n) repeat of NOS2A in diabetic retinopathy.

Accumulating evidence shows that the severity and rapidity of onset of diabetic retinopathy are influenced by genetic factors. Expression of the nitric oxide synthases is altered in the retinal vasculature in the early stages of diabetic retinopathy. We analyzed the allele distribution of a polymorphic pentanucleotide repeat within the 5' upstream promoter region of the NOS2A gene in samples of diabetic patients. In diabetic patients from Northern Ireland, the 14-repeat allele of the NOS2A marker was significantly associated with the absence of diabetic retinopathy. Carriers of this repeat had 0.21-fold the relative risk of developing diabetic retinopathy than noncarriers of this allele. They also had significantly fewer renal and cardiovascular complications. The ability of differing numbers of (CCTTT)(n) pentanucleotide repeats to induce transcription of the NOS2A gene was analyzed using a luciferase reporter gene assay in transfected colonic carcinoma cells. Interleukin 1beta (IL-1beta) induction was most effective in constructs carrying the 14-repeat allele. When cells were incubated in 25 mM glucose to mimic the diabetic state, IL-1beta induction was inhibited in all cases, but to a significantly lesser extent with the 14-repeat allele. These unique properties of the 14-repeat allele may confer selective advantages in diabetic individuals, which may delay or prevent microvascular complications of diabetes.

Adult↗

PubMed1999

Acquired rearrangement of an amplified epidermal growth factor receptor (EGFR) gene in a human glioblastoma xenograft.

Amplification of the epidermal growth factor receptor (EGFR) occurs in about 40% of human glioblastomas. In half of these cases, rearrangements of the amplified gene result in aberrant transcripts and proteins. The most frequent rearrangement affects the external domain of the receptor and results in nonbinding of ligand and constitutive activity. Less frequent rearrangements involve changes resulting in the loss of cytoplasmic amino acid sequences necessary for downregulation of the receptor following ligand binding. Here we report the development and selection for a rearranged amplified EGF receptor, which lacks cytoplasmic amino acid sequences in a human glioblastoma xenograft. An identical aberration has previously been reported in glioblastoma tissue. The patient tumor material, as well as the first passages of the xenograft showed amplification of the EGFR gene, but no evidence of gene rearrangement or an aberrant transcript. Interphase FISH data show the amplified gene on double minutes. Between passages 3 and 16, the growth rate of the xenograft almost doubled, the rearranged amplicon became dominant, as did the aberrant transcript, indicating selection under these conditions.

Animals↗

PubMed1999

Mutational profile of the PTEN gene in primary human astrocytic tumors and cultivated xenografts.

The genetic abnormality most frequently identified in glioblastomas is loss of alleles on chromosome 10. We have performed a comprehensive study of the PTEN tumor suppressor gene on 10q23, including loss of heterozygosity (LOH) analysis, multiplex PCR, mutation analysis, and reverse transcription PCR (RT-PCR). In total, 151 glioblastomas, 41 anaplastic astrocytomas, 15 astrocytomas, and 13 glioma cell lines were analyzed as well as 23 xenografts derived from primary glioblastomas, which allows a comparison of the PTEN gene status in primary tumors versus xenografts. Homozygous deletions were found in 7% of the glioblastomas and 40% showed mutation of a single retained allele. This mutation frequency is higher than reported previously. The large number of mutations identified allows the presentation of a mutational profile along the coding sequence. The majority of mutations appear to affect conserved residues or structurally conserved regions. PTEN alterations were selected for in xenografts, and there is evidence that they may even facilitate establishment of xenografts. No alterations were found in astrocytomas and only 5% of anaplastic astrocytomas had mutations. Thus, loss of wild type PTEN represents one of the major abnormalities associated with astrocytic tumor progression to glioblastoma and provides a strong selective growth advantage when cultivating glioblastoma tissue in xenografts. No correlation with EGFR amplification was evident.

Alleles↗

PubMed1999

Adaptation of the geminivirus bean yellow dwarf virus to dicotyledonous hosts involves both virion-sense and complementary-sense genes.

Bean yellow dwarf virus (BeYDV) and maize streak virus (MSV) belong to the geminivirus genus Mastrevirus and have host ranges confined to dicotyledonous and monocotyledonous species, respectively. To investigate viral determinants of host range specificity, chimeras were constructed by exchanging their coding and non-coding regions. BeYDV chimeras containing MSV ORF V1, ORF V2 or small intergenic region sequences, either individually or in various sequential combinations, replicated and produced virus particles in Nicotiana tabacum protoplasts. BeYDV chimeras containing MSV ORFs C1 and C2 and/or the large intergenic region were unable to replicate. None of the chimeras was able to systemically infect either N. benthamiana or maize. Complementation experiments using BeYDV chimeras containing MSV ORF V1 and/or ORF V2 suggest that expression of MSV movement protein and/or coat protein prevents BeYDV movement. The results demonstrate that factors involved in both viral DNA replication and virus movement are exclusively adapted to either monocotyledonous or dicotyledonous host backgrounds.

Adaptation, Physiological↗

PubMed1999

Catecholamine oxidative products, but not melanin, are produced by Cryptococcus neoformans during neuropathogenesis in mice.

Melanin has been proposed as a virulence factor in Cryptococcus neoformans, but its presence has not been shown unambiguously in vivo. Validated methods used previously to show production of cryptococcal eumelanin pigment in vitro (P. R. Williamson, K. Wakamatsu, and S. Ito, J. Bacteriol. 180:1570-1572, 1998) were used to assess for production of laccase-derived products in mouse brain of the Lacc+ strains, 2E-TUC, H99 (serotype A), and ATCC 34873 (serotype D), and the Lacc- strain, 2E-TU. Pyrrole-2,3, 5-tricarboxylic and pyrrole-2,3-dicarboxylic acid, specific degradation products of catecholamine derivatives such as melanin, were found in all Lacc+ strains, but not in the Lacc- strain, 2E-TU. However, the presence of melanin pigment itself could not be demonstrated in the same cells. Lack of the specific degradation products aminohydroxyphenylalanine and aminohydroxyphenylethylamine in Lacc+ strains upon hydriodic acid hydrolysis showed that pheomelanin was also not produced by the fungus in vivo. These are the first data to support the generation of catecholamine oxidation products by C. neoformans in vivo, but they do not support postenzymatic polymerization of these products to form typical eumelanin, as previously proposed.

Animals↗

PubMed1999

Laccase protects Cryptococcus neoformans from antifungal activity of alveolar macrophages.

While laccase of Cryptococcus neoformans is implicated in the virulence of the organism, our recent studies showing absence of melanin in the infected mouse brain has led us to a search for alternative roles for laccase in cryptococcosis. We investigated the role of laccase in protection of C. neoformans against murine alveolar macrophage (AM)-mediated antifungal activity by using a pair of congenic laccase-positive (2E-TUC) and laccase-deficient (2E-TU) strains. The laccase-positive cells with laccase derepression were more resistant to the antifungal activity of AM than a laccase-deficient strain ([28.9 +/- 1.2]% versus [40.2 +/- 2.6]% killing). Addition of L-dopa to Cryptococcus to produce melanin in a laccase-positive strain resulted in a slight increase in protection of C. neoformans from the antifungal activity of macrophages ([25.4 +/- 3.4]% versus [28.9 +/- 1.2]% killing). Recombinant cryptococcal laccase exhibited iron oxidase activity in converting Fe(II) to Fe(III). Moreover, recombinant laccase inhibited killing of C. neoformans by hydroxyl radicals catalyzed by iron in a cell-free system. Addition of the hydroxyl radical scavenger mannitol or dimethyl sulfoxide to AMs prior to the introduction of cryptococcal cells decreased killing of both strains and reduced the difference in susceptibility between the laccase-positive and laccase-deficient strains. Furthermore, laccase-mediated protection from AM killing was inhibited by the addition of Fe(II), presumably by overcoming the effects of the iron oxidase activity of cryptococcal laccase. These results suggest that the iron oxidase activity of laccase may protect C. neoformans from macrophages by oxidation of phagosomal iron to Fe(III) with a resultant decrease in hydroxyl radical formation.

Animals↗

PubMed1999

Differential expression of caprine beta-defensins in digestive and respiratory tissues.

We identified two novel beta-defensin precursors, preproGBD-1 and preproGBD-2, in the tissues of a goat. Although the precursors were identical in 96.8% of their bases and 88.2% (60 of 68) of their amino acids, preproGBD-1 was expressed principally in the tongue and respiratory tract, whereas preproGBD-2 expression predominated throughout the intestine. These findings exemplify the phenomenon of tissue-specific expression in a family of host defense peptides that arose before the avian and mammalian lineages diverged.

Amino Acid Sequence↗

PubMed1999

Genetic reassortment of avian, swine, and human influenza A viruses in American pigs.

In late summer through early winter of 1998, there were several outbreaks of respiratory disease in the swine herds of North Carolina, Texas, Minnesota, and Iowa. Four viral isolates from outbreaks in different states were analyzed genetically. Genotyping and phylogenetic analyses demonstrated that the four swine viruses had emerged through two different pathways. The North Carolina isolate is the product of genetic reassortment between H3N2 human and classic swine H1N1 influenza viruses, while the others arose from reassortment of human H3N2, classic swine H1N1, and avian viral genes. The hemagglutinin genes of the four isolates were all derived from the human H3N2 virus circulating in 1995. It remains to be determined if either of these recently emerged viruses will become established in the pigs in North America and whether they will become an economic burden.

Amino Acid Sequence↗

PubMed1999

T-cell vaccination alters the course of murine herpesvirus 68 infection and the establishment of viral latency in mice.

Diseases caused by gammaherpesviruses such as Epstein-Barr virus are a major health concern, and there is significant interest in developing vaccines against this class of viral infections. However, the requirements for effective control of gammaherpesvirus infection are only poorly understood. The recent development of the murine herpesvirus MHV-68 model provides an experimental tool to dissect the immune response to gammaherpesvirus infections. In this study, we investigated the impact of priming T cells specific for class I- and class II-restricted epitopes on the acute phase of the infection and the subsequent establishment of latency and infectious mononucleosis. The data show that vaccination with either major histocompatibility complex class I- or class II-restricted T-cell epitopes derived from lytic cycle proteins significantly reduced lung viral titers during the acute infection. Moreover, the peak level of latently infected spleen cells was significantly reduced following vaccination with immunodominant CD8(+) T-cell epitopes. However, this vaccination approach did not prevent the long-term establishment of latency or the development of the infectious mononucleosis-like syndrome in infected mice. Thus, the virus is able to establish latency efficiently despite strong immunological control of the lytic infection.

3T3 Cells↗

PubMed1999

p53 sites acetylated in vitro by PCAF and p300 are acetylated in vivo in response to DNA damage.

The p53 tumor suppressor protein is a sequence-specific transcription factor that modulates the response of cells to DNA damage. Recent studies suggest that full transcriptional activity of p53 requires the coactivators CREB binding protein (CBP)/p300 and PCAF. These coactivators interact with each other, and both possess intrinsic histone acetyltransferase activity. Furthermore, p300 acetylates p53 to activate its sequence-specific DNA binding activity in vitro. In this study, we demonstrate that PCAF also acetylates p53 in vitro at a lysine residue distinct from that acetylated by p300 and thereby increases p53's ability to bind to its cognate DNA site. We have generated antibodies to acetylated p53 peptides at either of the two lysine residues that are targeted by PCAF or p300 and have demonstrated that these antibodies are highly specific for both acetylation and the particular site. Using these antibodies, we detect acetylation of these sites in vivo, and interestingly, acetylation at both sites increases in response to DNA-damaging agents. These data indicate that site-specific acetylation of p53 increases under physiological conditions that activate p53 and identify CBP/p300 and PCAF as the probable enzymes that modify p53 in vivo.

Acetylation↗

PubMed1999

Decreased visceral adiposity accounts for leptin effect on hepatic but not peripheral insulin action.

Leptin decreases visceral fat (VF) and increases peripheral and hepatic insulin action. Here, we generated similar decreases in VF using leptin (Lep), beta(3)-adrenoreceptor agonism (beta3), or food restriction (FR) and asked whether insulin action would be equally improved. For 8 days before the in vivo study, Sprague-Dawley rats (n = 24) were either fed ad libitum [control (Con)], treated with Lep or beta3 (CL-316,243) by implanted osmotic mini-pumps, or treated with FR. Total VF was similarly decreased in the latter three groups (Lep, 3.11 +/- 0.96 g; beta3, 2.87 +/- 0.48 g; and FR, 3.54 +/- 0.77 g compared with 6.91 +/- 1.41 g in Con; P < 0.001) independent of total fat mass (by (3)H(2)O) and food intake. Insulin (3 mU. kg(-1). min(-1)) clamp studies were performed to assess hepatic and peripheral insulin sensitivity. Decreased VF resulted in similar and marked improvements in insulin action on glucose production (GP) (Lep, 1.19 +/- 0.51; beta3, 1.46 +/- 0.68; FR, 2.27 +/-0.71 compared with 6.06 +/- 0.70 mg. kg(-1). min(-1) in Con; P < 0.001). By contrast, reduction in VF by beta3 and FR failed to reproduce the stimulation of insulin-mediated glucose uptake ( approximately 60%), glycogen synthesis ( approximately 80%), and glycolysis ( approximately 25%) observed with Lep. We conclude that 1) a moderate decrease in VF uniformly leads to a marked increase in hepatic insulin action, but 2) the effects of leptin on peripheral insulin action are not due to the associated changes in VF or beta3 activation.

Adipose Tissue↗

PubMed1999

Cellular properties of lateral spinal nucleus neurons in the rat L6-S1 spinal cord.

Conventional intracellular recordings were made from 26 lateral spinal nucleus (LSN) neurons in slices of L6-S1 spinal cord from 10- to 15-day-old rats. At rest, LSN neurons did not fire spontaneous action potentials. With injection of a positive current pulse, action potentials had an amplitude of 72 +/- 7 (SD) mV and duration at half-peak height of 0.75 +/- 0.22 ms. Action potentials were followed by an afterpotential. Most LSN neurons (13/17) exhibited only an afterhyperpolarization (AHP); four neurons exhibited both a fast and a slow AHP separated by an afterdepolarization (ADP). For LSN neurons that exhibited only an AHP, a slow ADP could be identified during bath application of apamin (100 nM). Four of 11 LSN neurons showed a postinhibitory rebound (PIR). Two types of PIR were noted, one with high threshold and low amplitude and the other with low threshold and high amplitude. The PIR with high amplitude was partially blocked in 0 mM Ca2+/high Mg2+ (10 mM) recording solution. Repetitive firing properties were examined in 17 LSN neurons. On the basis of the ratio of the slopes between initial instantaneous firing and steady-state firing frequencies, neurons with low spike frequency adaptation (SFA, 8/17) and high SFA (4/17) were identified. In addition, 2/17 LSN neurons exhibited biphasic repetitive firing patterns, which were composed of a fast SFA, delayed excitation, and low SFA; another two neurons showed only delayed excitation. Plateau potentials also were found in two LSN neurons. Dorsal root stimulation revealed that most LSN neurons (12/13) had polysynaptic postsynaptic potentials (PSP); only one neuron exhibited a monosynaptic PSP. Electrical stimulation of the dorsal root evoked prolonged discharges in low SFA neurons and a short discharge in high SFA neurons. Intrinsic properties were modulated by bath application of substance P (SP). Membrane potentials were depolarized in all eight LSN neurons tested, and membrane resistance was either increased (n = 3) or decreased (n = 2). Both instantaneous firing and steady-state firing were facilitated by SP. In addition, oscillation of membrane potentials were induced in three LSN neurons. These results demonstrate that LSN neurons exhibit a variety of intrinsic properties, which may significantly contribute to sensory processing, including nociceptive processing.

Action Potentials↗

PubMed1999

A vascular bed-specific pathway.

The endothelial nitric oxide synthase (eNOS) gene is induced by a variety of extracellular signals under both in vitro and in vivo conditions. To gain insight into the mechanisms underlying environmental regulation of eNos expression, transgenic mice were generated with the 1,600-bp 5' flanking region of the human eNos promoter coupled to the coding region of the LacZ gene. In multiple independent lines of mice, transgene expression was detected within the endothelium of the brain, heart, skeletal muscle, and aorta. beta-galactosidase activity was consistently absent in the vascular beds of the liver, kidney, and spleen. In stable transfection assays of murine endothelial progenitor cells, the 1,600-bp promoter region was selectively induced by conditioned media from cardiac myocytes, skeletal myocytes, and brain astrocytes. Cardiac myocyte-mediated induction was partly abrogated by neutralizing anti-platelet-derived growth factor (PDGF) antibodies. In addition, promoter activity was upregulated by PDGF-AB. Analysis of promoter deletions revealed that a PDGF response element lies between -744 and -1,600 relative to the start site of transcription, whereas a PDGF-independent cardiac myocyte response element is present within the first 166 bp of the 5' flanking region. Taken together, these results suggest that the eNos gene is regulated in the cardiac endothelium by both a PDGF-dependent and PDGF-independent microvascular bed-specific signaling pathway.

Animals↗

PubMed1999

The role of the renin-angiotensin and cardiac sympathetic nervous systems in the development of hypertension and left ventricular hypertrophy in spontaneously hypertensive rats.

To elucidate the relationship between the development of left ventricular hypertrophy (LVH) in hypertension and the development of both the cardiac sympathetic nervous and renin-angiotensin systems, as measured by norepinephrine and angiotensin II levels, respectively. In this longitudinal study, we compared blood pressure (BP), left ventricular weight, and norepinephrine (NE) and angiotensin II (Ang II) concentrations, in Spontaneously Hypertensive Rats (SHR) and age-matched Wistar-Kyoto (WKY) rats at 5, 10, 15, 20, and 28 wk of age. Blood pressure, plasma and ventricular Ang II and tissue NE were measured by the tail-cuff method, radioimmunoassay, and high-performance liquid chromatography (HPLC), respectively. At 5 wk, systolic blood pressure was the same in both strains. But the left ventricular plus septum weight to body weight (LVSW/BW) ratio was higher in SHR than in WKY rats (p < 0.01), which finding may have been related to the increased cardiac tissue NE concentration, and this increase tended to parallel the rise in blood pressure. Both left ventricle and forelimb muscle NE concentrations were significantly higher in SHR than in WKY rats at 5, 10, and 15 wk of age (p < 0.01, respectively), and were similar at 20 and 28 wk of age. The heart and plasma Ang II levels decreased with age, which results were in keeping with the known developmental tendencies of the biological aging progress. There was no significant difference in plasma Ang II levels between the two strains from 5 to 20 wk, whereas these levels were remarkably higher in WKY than in SHR rats at 28 wk (p< 0.01). Otherwise, the left ventricular tissue Ang II concentrations were significantly higher in SHR than in WKY rats at the late stage (from 15 to 28 wk), which may have contributed to the late-stage cardiac hypertrophy. These results suggested that the sympathetic nervous system (SNS) and the renin-angiotensin-system (RAS) in SHR may contribute to the pathogenesis of hypertension and LVH at the early and late stages, respectively.

Animals↗