archives@tulane.edu / Rupture of atherosclerotic plaque can cause acute life-threatening events such as myocardial infarction and ischemic stroke; therefore, there is much interest in developing therapies aimed at increasing plaque stability. More stable lesions are characterized as having high collagen content and containing a large number of vascular smooth muscle cells (SMCs) of contractile/differentiated phenotype. In our previous studies using an apolipoprotein E-deficient (Apoe -/-) mouse model of atherosclerosis, we found that insulin-like growth factor-1 (IGF-1)-infusion not only reduced total plaque burden, but also increased collagen expression and the number of alpha-smooth muscle actin (αSMA)-positive cells in plaque. In this study, we identify cellular mechanisms responsible for these observations. We found that in human aortic smooth muscle cells (HASMCs) grown in culture, IGF-1 post-transcriptionally upregulated expression of the procollagen type I alpha-1 subunit (pro-α1(I)) as well as contractile proteins, αSMA and smooth muscle 22-alpha (SM22α), via a PI3K-dependent but Erk1/2- and mTOR-independent signaling mechanism. Furthermore, experiments using an inhibitor of collagen synthesis or a blocking antibody against the alpha2beta1-integrin (α2β1) suggested that interaction with collagen type I promotes HASMC contractile phenotype. To elucidate mechanisms underlying IGF-1 upregulation of collagen synthesis we investigated the effect of IGF-1 on the mRNA-binding protein, la ribonucleoprotein domain family member 6 (LARP6), which had been shown to bind a conserved stem-loop secondary motif in the 5'UTR of COL1a1 and COL1a2 mRNA. IGF-1 rapidly increased LARP6 expression in HASMCs leading to increased COL1a1 and COL1a2 mRNA bound LARP6 and increased synthesis of collagen type I. Mutation of the 5'stem-loop of Col1a1 mRNA (that inhibited binding by LARP6) or overexpression of a 5'stem-loop RNA molecular decoy (that sequesters LARP6) both prevented the ability of IGF-1 to increase pro-α1(I) synthesis as well as mature α1(I) expression in cultured medium. Furthermore, IGF-1-infusion in Apoe -/- mice increased LARP6 and pro-α1(I) expression in aortic lysates, and SMC-specific IGF-1-overexpression in transgenic mice robustly increased collagen fibrillogenesis in atherosclerotic plaque. In conclusion, this work identifies LARP6 as a critical mediator by which IGF-1 augments synthesis of collagen type I in vascular smooth muscle, and uncovers key mechanisms whereby IGF-1 promotes atherosclerotic plaque stability. / 1 / Admin

O crescimento compensatório pode ser uma ferramenta interessante em sistemas de criação de bovinos de corte, uma vez que os animais que passam por crescimento compensatório são mais eficientes, diminuindo o custo com alimentação. É bem aceito que a nutrição é capaz de influenciar a idade à puberdade de novilhas, no entanto, pouco se sabe sobre o efeito do crescimento compensatório na puberdade de novilhas Nelore. O objetivo deste trabalho foi avaliar o efeito de ritmos de crescimento e crescimento compensatório sobre a idade e peso à puberdade de novilhas Nelore. Para isso, foram utilizadas 120 novilhas da raça Nelore, desmamadas com oito meses de idade e filhas de 6 touros que foram alocadas em quatro tratamentos de acordo com o peso inicial de 180 ± 8,6 kg. O período experimental foi dos 8 aos 18 meses de idade. Tratamentos: 1) GMD elevado (CMS d libitum), cerca de 1kg/dia, durante todo o período experimental (ALTO). 2) GMD médio (0,6kg/dia) durante o período experimental (MÉDIO). 3) Restrição alimentar por 4 meses (0,2kg/dia), seguido de CMS ad libitum com crescimento compensatório (RESTRITO). 4) CMS ad libitum (GMD elevado) por dois meses, alternando com restrição alimentar (0,2kg/dia), durante um período total de 10 meses (ALTERNADO). A restrição alimentar foi realizada através da restrição quantitativa do CMS, e o crescimento compensatório e o GMD alto foram obtidos através do CMS ad libitum. As novilhas passaram por exame ginecológico semanalmente e a manifestação da puberdade foi acompanhada por meio de US (presença de CL) e colheita de sangue (determinação de P4). Também foi determinada a concentração de IGF-1 (8, 10, 12, 14, 16 e 18 meses de idade e no momento da puberdade) e leptina (8, 11 e 18 meses de idade e no momento da puberdade). Ao final do experimento, as novilhas que não entraram em puberdade foram submetidas a um protocolo de indução de puberdade com P4. O delineamento utilizado foi em blocos casualizados incompletos (touro), sendo as variáveis contínuas analisadas pelo procedimento MIXED e as variáveis binomiais avaliadas pelos procedimentos GLIMMIX ou LIFETEST quando avaliadas as curvas de sobrevivência, todos procedimentos procedimento do SAS 9,3. Não houve diferença na porcentagem de novilhas púberes aos 18 meses de idade entre os tratamentos. O peso a puberdade e a idade a puberdade também não diferiram entre os tratamentos. Entretanto, o GMD ao longo do experimento (P<0,01) e até a puberdade (P<0,01) foi maior nas novilhas submetidas ao tratamento ALTO diferindo dos demais. Ainda, as novilhas submetidas ao tratamento ALTO apresentaram maior CMS (P<0,01) que o RESTRITO, e a magnitude dessa diferença foi de 20%. Em relação as análises de IGF-1, houve interação entre tratamento e idade (P=0,02), no qual as novilhas submetidas ao tratamento ALTERNADO apresentaram maior concentração de IGF-1 aos 12 e aos 16 meses de idade quando comparado com os outros tratamentos. A concentração de leptina foi maior (P=0,04) nas novilhas submetidas ao tratamento ALTO quando comparado com as novilhas submetidas aos tratamentos MÉDIO. Em relação a porcentagem de novilhas que responderam a indução, não houve diferença entre os tratamentos, sendo que cerca de 80% das novilhas responderam à indução. Novilhas passando por um período de restrição, seguido por um suporte nutricional eficiente, foram capazes de alcançar a puberdade em idade e peso semelhantes daquelas que não passaram por restrição. Ainda, as novilhas submetidas à restrição alimentar apresentaram menor CMS. Assim, o crescimento compensatório foi uma estratégia nutricional eficiente em reduzir o CMS, melhorando a eficiência alimentar e não prejudicou a idade à puberdade. / The aim of this study was to evaluate the effect of growth rates and compensatory growth on the age and weight at puberty of heifers. For that, 120 Nellore heifers, weaned at eight months of age, daughters of 6 bulls, with initial body weight of 180±8.6 kg were used. The experimental design was randomized blocks (sires). The experimental period was from 8 to 18 months of age. Treatments were: 1) High ADG (ad libitum DMI) throughout the experimental period (HIGH), 2) Mid ADG (0.6kg/d) throughout the experimental period (MID), 3) Feed restriction for 4 months (0.2kg/d), followed by ad libitum DMI with compensatory growth (RESTRICT), 4) ad libitum DMI (High ADG) for 2 months, alternating with feed restriction (0.2kg/d), throughout a period of 10 months (ALTERNATE). The diet was composed of ground corn (70%), sugarcane bagasse (12%), soybean meal (16%), mineral mixture (1%) and urea (1%). Weekly gynecological examination was performed, whereas the manifestation of puberty was monitored by means of ultrasonography. Additional blood samples were collected for determination of IGF-1 and leptin. At the end of the experimental period, the heifers that did not reach puberty were submitted to a puberty induction protocol with progesterone. The continuous variables were analyzed by the MIXED procedure and the binomial variables evaluated by the procedures GLIMMIX (SAS 9.3). There was no difference in the percentage of pubertal heifers at 18 months of age, weight and age at puberty between treatments. However, the ADG throughout the experiment (P<0.01) and until puberty (P<0.01) was greater in heifers submitted to HIGH, compared to the other treatments. Moreover, heifers submitted to HIGH had greater DMI (P<0.01) than the RESTRICT, with the magnitude of this difference of 20%. The feed efficiency (P<0.01) were 0.128, 0.120, 0.146 and 0.113 for HIGH, MID, RESTRICT and ALTERNATE respectively. There was treatment x age interaction (P=0.02) for IGF-1, in which the ALTERNATE had greater concentration of IGF-1 at 12 and 16 months of age when compared to the other treatments. The leptin concentration was greater (P=0.03) in HIGH when compared to the MID. In relation to the percentage of heifers that responded to the induction, there was no difference between treatments and about 80% of the heifers responded to induction. Heifers submitted to feed restriction had a reduced DMI, hence, the compensatory growth was an efficient nutritional strategy to feed efficiency and did not differ age at puberty.

O crescimento compensatório pode ser uma ferramenta interessante em sistemas de criação de bovinos de corte, uma vez que os animais que passam por crescimento compensatório são mais eficientes, diminuindo o custo com alimentação. É bem aceito que a nutrição é capaz de influenciar a idade à puberdade de novilhas, no entanto, pouco se sabe sobre o efeito do crescimento compensatório na puberdade de novilhas Nelore. O objetivo deste trabalho foi avaliar o efeito de ritmos de crescimento e crescimento compensatório sobre a idade e peso à puberdade de novilhas Nelore. Para isso, foram utilizadas 120 novilhas da raça Nelore, desmamadas com oito meses de idade e filhas de 6 touros que foram alocadas em quatro tratamentos de acordo com o peso inicial de 180 ± 8,6 kg. O período experimental foi dos 8 aos 18 meses de idade. Tratamentos: 1) GMD elevado (CMS d libitum), cerca de 1kg/dia, durante todo o período experimental (ALTO). 2) GMD médio (0,6kg/dia) durante o período experimental (MÉDIO). 3) Restrição alimentar por 4 meses (0,2kg/dia), seguido de CMS ad libitum com crescimento compensatório (RESTRITO). 4) CMS ad libitum (GMD elevado) por dois meses, alternando com restrição alimentar (0,2kg/dia), durante um período total de 10 meses (ALTERNADO). A restrição alimentar foi realizada através da restrição quantitativa do CMS, e o crescimento compensatório e o GMD alto foram obtidos através do CMS ad libitum. As novilhas passaram por exame ginecológico semanalmente e a manifestação da puberdade foi acompanhada por meio de US (presença de CL) e colheita de sangue (determinação de P4). Também foi determinada a concentração de IGF-1 (8, 10, 12, 14, 16 e 18 meses de idade e no momento da puberdade) e leptina (8, 11 e 18 meses de idade e no momento da puberdade). Ao final do experimento, as novilhas que não entraram em puberdade foram submetidas a um protocolo de indução de puberdade com P4. O delineamento utilizado foi em blocos casualizados incompletos (touro), sendo as variáveis contínuas analisadas pelo procedimento MIXED e as variáveis binomiais avaliadas pelos procedimentos GLIMMIX ou LIFETEST quando avaliadas as curvas de sobrevivência, todos procedimentos procedimento do SAS 9,3. Não houve diferença na porcentagem de novilhas púberes aos 18 meses de idade entre os tratamentos. O peso a puberdade e a idade a puberdade também não diferiram entre os tratamentos. Entretanto, o GMD ao longo do experimento (P<0,01) e até a puberdade (P<0,01) foi maior nas novilhas submetidas ao tratamento ALTO diferindo dos demais. Ainda, as novilhas submetidas ao tratamento ALTO apresentaram maior CMS (P<0,01) que o RESTRITO, e a magnitude dessa diferença foi de 20%. Em relação as análises de IGF-1, houve interação entre tratamento e idade (P=0,02), no qual as novilhas submetidas ao tratamento ALTERNADO apresentaram maior concentração de IGF-1 aos 12 e aos 16 meses de idade quando comparado com os outros tratamentos. A concentração de leptina foi maior (P=0,04) nas novilhas submetidas ao tratamento ALTO quando comparado com as novilhas submetidas aos tratamentos MÉDIO. Em relação a porcentagem de novilhas que responderam a indução, não houve diferença entre os tratamentos, sendo que cerca de 80% das novilhas responderam à indução. Novilhas passando por um período de restrição, seguido por um suporte nutricional eficiente, foram capazes de alcançar a puberdade em idade e peso semelhantes daquelas que não passaram por restrição. Ainda, as novilhas submetidas à restrição alimentar apresentaram menor CMS. Assim, o crescimento compensatório foi uma estratégia nutricional eficiente em reduzir o CMS, melhorando a eficiência alimentar e não prejudicou a idade à puberdade. / The aim of this study was to evaluate the effect of growth rates and compensatory growth on the age and weight at puberty of heifers. For that, 120 Nellore heifers, weaned at eight months of age, daughters of 6 bulls, with initial body weight of 180±8.6 kg were used. The experimental design was randomized blocks (sires). The experimental period was from 8 to 18 months of age. Treatments were: 1) High ADG (ad libitum DMI) throughout the experimental period (HIGH), 2) Mid ADG (0.6kg/d) throughout the experimental period (MID), 3) Feed restriction for 4 months (0.2kg/d), followed by ad libitum DMI with compensatory growth (RESTRICT), 4) ad libitum DMI (High ADG) for 2 months, alternating with feed restriction (0.2kg/d), throughout a period of 10 months (ALTERNATE). The diet was composed of ground corn (70%), sugarcane bagasse (12%), soybean meal (16%), mineral mixture (1%) and urea (1%). Weekly gynecological examination was performed, whereas the manifestation of puberty was monitored by means of ultrasonography. Additional blood samples were collected for determination of IGF-1 and leptin. At the end of the experimental period, the heifers that did not reach puberty were submitted to a puberty induction protocol with progesterone. The continuous variables were analyzed by the MIXED procedure and the binomial variables evaluated by the procedures GLIMMIX (SAS 9.3). There was no difference in the percentage of pubertal heifers at 18 months of age, weight and age at puberty between treatments. However, the ADG throughout the experiment (P<0.01) and until puberty (P<0.01) was greater in heifers submitted to HIGH, compared to the other treatments. Moreover, heifers submitted to HIGH had greater DMI (P<0.01) than the RESTRICT, with the magnitude of this difference of 20%. The feed efficiency (P<0.01) were 0.128, 0.120, 0.146 and 0.113 for HIGH, MID, RESTRICT and ALTERNATE respectively. There was treatment x age interaction (P=0.02) for IGF-1, in which the ALTERNATE had greater concentration of IGF-1 at 12 and 16 months of age when compared to the other treatments. The leptin concentration was greater (P=0.03) in HIGH when compared to the MID. In relation to the percentage of heifers that responded to the induction, there was no difference between treatments and about 80% of the heifers responded to induction. Heifers submitted to feed restriction had a reduced DMI, hence, the compensatory growth was an efficient nutritional strategy to feed efficiency and did not differ age at puberty.

Insulin and insulin-like growth factor 1 (IGF-1) and 2 (IGF-2) are related protein hormones with different but overlapping biological functions. All the hormones interact with a receptor within the insulin-IGF system (insulin receptor A and B, IGF-1 receptor), however with different affinity. The different interaction with individual receptors is just one of the main tools for regulation of the system that is essential for the proper functioning of the organism. Although the residues directly interacting with receptors are mainly located in A and B domains, the C and D domains probably play a role in receptor specificity. Here, we firstly focused on the impact of D domains of IGF-1 and 2 (D1 and D2 domains) and C domain of IGF- 2 (C2 domain). To probe the impact of C and D domains, we prepared insulin analogues containing a part of or an entire domain following a pattern seen in IGFs. The receptor-binding affinities of these analogues and their receptor autophosphorylation potentials were characterised. Our results revealed that the initial part of D1 domain has a detrimental effect on IR affinity that is only slightly enhanced by the rest of the D1 domain. D2 domain has rather neutral effect on IR affinity. We further showed that the addition of amino acids derived from the C2 domain to the...

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The role of the IGF system during intestinal development of the pig, and in particular the significance of dietary IGF-I was investigated. Significant concentrations of IGF-I and IGFBP were measured in milk and colostrum and in vitro immunoaffinity chromatography studies confirmed IGF-I stability in the presence of newborn and suckled intestinal contents. Specific IGF-I receptors were identified on apical and basolateral membranes, and the cytoplasm of villus/crypt enterocytes. Receptor binding data revealed binding to a single site, with an affinity of 1nM. Receptor affinity remained constant during development but in apical microvillar membranes, IGF-I receptors were transiently up-regulated in suckled animals. The specificity of receptors was confirmed using competition binding and affinity crosslinking studies, and the functional activity of receptors demonstrated using an in vitro receptor autophosphorylation assay. In Caco-2 intestinal cells IGF-I binding and IGF-I receptor mRNA expression was significantly increased in the presence of 7 and 14 day milk, suggesting that milk-borne factors may regulate the up-regulation observed in vivo. In vivo experiments were undertaken using colostrum-fed and colostrum-deprived artificially-reared pigs. Significant differences in plasma IGF-I and IGF binding proteins were observed in the IGF- treated animals compared to controls suggesting that IGF-I remained bioactive in the intestine and was transported to the circulation. The in vivo effects of IGF-I were modulated by early nutrition. Plasma IGF-I increased in colostrum-deprived animals, whereas in colostrum-fed animals levels decreased.

Durante a endotoxemia, observa-se alteração no eixo hormônio do crescimento(GH)/fator de crescimento semelhante à insulina (IGF)-1. Acredita-se que o aumento de citocinas pró-inflamatórias seja responsável por essa alteração, apesar do mecanismo para essa alteração ainda não estar completamente elucidado. A ghrelina é um hormônio peptídico que apresenta propriedades anti-inflamatórias, e, portanto, pode contribuir para a manutenção da integridade do eixo GH/IGF-1. O objetivo do presente estudo foi avaliar o efeito do tratamento sistêmico de ghrelina sobre o eixo GH/IGF-1 em ratos Wistar submetidos à endotoxemia. Para a indução da endotoxemia, foi administrado lipopolissacarídeo (LPS; 5mg/kg intraperitoneal) sistemicamente. Os animais foram tratados com ghrelina (15nmol/kg; endovenoso) concomitantemente à administração de LPS e tiveram o sangue e o fígado coletados após 2h,6h ou 12h. Foram quantificadas a concentração sanguínea do fator de necrose tumoral alfa (TNF-?), interleucina (IL)-1?, IL-6, nitrato, corticosterona, GH, IGF-1 e ghrelina endógena, assim como a concentração hepática de TNF-?, IL-1? e IL-6. O TNF-?, IL-1?, IL-6, GH, IGF-1 e ghrelina endógena foram quantificados pela técnica de ELISA. A corticosterona foi quantificada pela técnica de radioimunoensaio. O Nitrato foi quantificado pela técnica de quimioluminescência. Também foram quantificadas a expressão proteica hepática do receptor do hormônio secretador do GH (GHSR-1a) e do receptor do GH (GHR) pela técnica de Western Blott, bem como a expressão gênica hepática de IGF-1 e GHR pela técnica de PCR-RT. Os ratos submetidos à endotoxemia apresentaram redução sérica de IGF-1 e de GH, caracterizando a alteração do eixo GH/IGF-1. Os animais endotoxêmicos e tratados com ghrelina apresentaram menor redução dos níveis circulantes de IGF-1, além de apresentarem menores níveis de TNF-?, IL-1?, IL-6 e nitrato após administração de LPS. A menor redução de IGF-1 circulante após o tratamento com ghrelina não foi relacionada a alterações na expressão proteica de GHSR-1a ou GHR, nem relacionada a alterações na expressão gênica de IGF-1 ou GHR nos intervalos de tempo analisados. Portanto, a propriedade anti-inflamatória da ghrelina levou à redução do aumento dos mediadores pró-inflamatórios e contribuiu para a manutenção da integridade do eixo GH/IGF-1 ao atenuar a queda na concentração sanguínea de IGF-1. Endotoxemia. Inflamação. Eixo GH/IGF-1 / During the endotoxemia it is possible to observe a change on the growth hormone (GH) /insulin-like growth factor (IGF)-1 axis. It is believed that the pro inflammatory cytokines increase is responsible for this change even not having the mechanism for this change completely elucidated. The ghrelin is a peptidic hormone which has antiinflammatory properties and, because of that, can contribute to the GH/IGF-1 axis integrity maintenance. This research goal is to evaluate the ghrelin systemic treatment effect on the GH/IGF-1 axis on Wistar rats submitted to endotoxemia. To induct the endotoxemia it was given systemically to the rats a lipopolysaccharide (LPS; 5mg/kg intraperitoneal). The animals were treated with ghrelin (15nmol/kg; intravenous) while receiving the LPS and they had their blood and liver collected after 2h, 6h or 12h. Blood concentration of alfa tumoral necrose (TNF-?), interleukin (IL)-1?, IL-6, nitrate, corticosterone, GH, IGF-1 and endogenous ghrelin were quantified as well as their TNF-?, IL-1? e IL-6 hepatic concentration. The TNF-?, IL-1?, IL-6, GH, IGF-1 and the endogenous ghrelin were quantified through the ELISA technique. The corticosterone was quantified through the radioimmunoassay technique. The nitrate was quantified through the chemiluminescence technique. The hepatic protein expression from the growth hormone secretagogue receptor (GHSR)-1a and the receptor of the GH (GHR) were quantified through the Western Blott technique and the IGF-1 and the GHR hepatic gene expression through the PCR-RT technique. The rats submitted to the endotoxemia presented an IGF-1 and a GH serum decrease characterizing a change on the GH/IGF-1 axis. The endotoxemic animals treated with ghrelin showed a smaller reduction of the IGF-1 circulating levels besides presenting a smaller TNF-?, IL-1?, IL- 6 and nitrate levels after receiving the LPS. The smallest IGF-1 circulating decrease, after the treatment with ghrelin, was related neither to the changes on the GHSR-1a or GHR protein expressions nor to the IGF-1 or GHR gene expressions during the analyzed time intervals. Therefore, the ghrelin anti-inflammatory property inflected a reduction of the pro-inflammatory mediators increase and contributed for the GH/IGF- 1 axis integrity maintenance while mitigating the IGF-1 blood concentration fall.

A distrofia muscular de Duchenne (DMD) é uma doença de caráter hereditário recessivo ligado ao cromossomo X, que determina a ausência da distrofia, a responsável pela progressiva degenaração muscular observada no DMD. Embora não expresse o fenótipo, a camundongo mdx apresenta a ausência da distrofia e o mais comum modelo animal experimental para estudar as repercursões da DMD em muitos orgãos. Este estudo foi realizado na cartilagem do processo condilar da mandíbula de mdx, um importante sítio de crescimento craniofacial. Assim, o PC dos mdx de 4 (G1) e 10 (G2) semanas e dos respectivos controles (camundongos c57BL/10 mice) foram avaliados usando as técnicas de microscopia de luz (H.E, Picrosirius e Safranina-O) e de imunohistoquímica (IGF e IGF-IR). Em ambos os grupos, não houve diferença estatísticamente significante na área do PC e comparação aos controles. O número de e a área dos condrócitos, bem como, a quantidade de matriz extracelular (MEC) forma menores nos grupos mdx. A imunorreatividade para ambos, IGF-I e IGF-IR, proporcionalmente maiores nos grupos mdx. Os dados quantitativos e predominância do colágeno tipo I nos grupos mdx, sugere um processo precoce de envelhecimento na cartilagem do PC desses animais. / The duchenne muscular dystrophy (DMD) is a recessive hereditary disease linked to X-chromossome that determines teh dystrophin abstence, the responsible for progressive muscle degeneration observed in DMD. Although not exhibit the phenotype, the MDX mouse reveal abstence of dystrophin and is the most common experimental animal model for DMD studies in many organs. This study was performed in the articular cartilage of the mandibular condylar process (PC) of MDX, an important site of craniofacial growth. Thus the PC of MDX and respective controls (C57BL/10 mice) were evaluated at the ages of 4 (G1) and 10 (G2) weeks using ligth microscopy (H.E, Picrosirius e Safranin-O) and immunohistochemical (IGF-I e IGF-IR) tecniques. In both groups, there was no statistical significant difference in PC area of the mdx and the respective controls. The number and area of the chondrocytes, as well as the amout of extracellular matrix (MEC) were lower in MDX groups. The immunoreactivity for both, IGF-I and IGF-IR, were propostionally higher im MDX groups. The quantitative data and the predominance of collagen type i fibers in the MDX groups suggest a premature aging process of the PC in these animals.

Insulin-like growth factor 1 (IGF-1) was considered as a factor potentially involved in arterial hypertension because of its effects on vascular tone. Several studies have suggested that IGF-1 might play an important role in the cardiovascular system for regulation of blood pressure. Previously, microinjection of insulin into the NTS of rats preceded prominent depressor and bradycardic and activates the PI3K downstream Akt. The aims of this study was to compare the cardiovascular responses induced by IGF-1 and to investigate the mechanisms of IGF-1induced signaling pathway in the nucleus tractus solitarius (NTS) between spontaneously hypertensive rat (SHR) and normotensive Wistar-Kyoto rat (WKY) at 8/16 weeks old. The results indicate that microinjection of IGF-1 into the NTS of WKY and SHR produced dramatically depressor and bradycardic effects. The cardiovascular effects evoked by IGF-1 are less in SHR than WKY rats. The defect in IGF-1 vascular action is also present in young spontaneously hypertensive rats (age 8 weeks). Pretreatment with the phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002 significantly attenuated the responses evoked by microinjection of IGF-1 in both SHR and WKY at 8/16 weeks old. Moreover, mitogen-activated protein kinase kinase (p44/p42MAPK) inhibitor PD98059 administration attenuated the cardiovascular effects of IGF-1 in WKY at 8/16 weeks old but had no effect in SHR at age matched. In conclusion, both IGF-1/PI3K and p44/p42MAPK signal transduction pathways are involved in controlling central cardiovascular effects in WKY, whereas PI3K but not p44/p42MAPK signaling pathway is involved in SHR. This different condition suggests that such insensitive pathway may play a causative role in the development of hypertension.

The insulin-like growth factor (IGF) system is an important determinant of growth in animals and recent findings suggest that immunomodulatory activity may regulate the IGF system independent of nutritional parameters. A cross-sectional study of the hepatic gene expression of the IGF system (IGF-1, IGFBP-3, GHR) and immunomodulatory agents (CRP, Hp, SAA, IL-1β, IL-6, IL-10, IL-18, IFN-α, IFN-γ, TNF-α) in nursery pigs (n=168) from 8 farms was completed. Production parameters and swine pathogens (Salmonella spp., L. intracellularis, Brachyspira spp., ETEC, MRSA, SIV, and PRRSV) were also assessed in relation to the IGF system. Hepatic expression of IGF-1, IGFBP-3, and GHR was associated with growth performance and was inversely associated with several immunomodulatory agents including Hp, SAA, IL-1β, IL-18, and TNF-α. These findings suggest that elevated levels of proinflammatory agents may dysregulate the transcriptional expression of the IGF system in hepatic tissue and consequently affect the growth and metabolism of nursery pigs. / Swine Innovation Porc