Influence of atenolol and nifedipine on nitric oxide deficient cardiomyocyte hypertrophy and expression of the cardio-endocrine peptide intermedin and its receptor components.

BACKGROUND/AIMS: Chronic inhibition of nitric oxide (NO) synthesis is associated with hypertension, myocardial ischemia, oxidative stress and hypertrophy; expression of adrenomedullin (AM) and intermedin (IMD) and their receptor activity modifying proteins (RAMPs 1-3) is augmented in cardiomyocytes, indicating that the myocardial AM/ IMD system may be activated in response to pressure loading and ischemic insult. The aim was to examine effects on (i) parameters of cardiomyocyte hypertrophy and on (ii) expression of AM and IMD and their receptor components in NO-deficient cardiomyocytes of an intervention chosen specifically for ability to alleviate pressure loading and ischemic injury concurrently. METHODS: The NO synthesis inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME, 35 mg.kg(-1).day(-1)) was given to rats for 8 weeks, with/ without concurrent administration of beta-adrenoceptor antagonist, atenolol (25 mg.kg(-1).day(-1)) / calcium channel blocker, nifedipine (20mg.kg(-1).day(-1)). RESULTS: In L-NAME treated rats, atenolol / nifedipine abolished increases in systolic blood pressure and plasma AM and IMD levels and in left ventricular cardiomyocytes: (i) normalized increased cell width and mRNA expression of hypertrophic (sk-alpha-actin) and cardio-endocrine (ANP, BNP, ET) genes; (ii) normalized augmented membrane protein oxidation; (iii) normalized mRNA expression of AM, IMD, RAMP1, RAMP2 and RAMP3. CONCLUSIONS: normalization of blood pressure and membrane oxidant status together with prevention of hypertrophy and normalization of the augmented expression of AM, IMD and their receptor components in NO-deficient cardiomyocytes by atenolol / nifedipine supports involvement of both pressure loading and ischemic insult in stimulating cardiomyocyte hypertrophy and induction of these counter-regulatory peptides and their receptor components. Attenuation of augmented expression of IMD in this model cannot however be explained simply by prevention of cardiomyocyte hypertrophy.

Quantification of Hox and Surfactant Protein-B Transcription during Murine Lung Development.

Abstract BACKGROUND: Genetic processes underlying fetal lung development and maturation are incompletely understood. Better knowledge of these processes would provide insights into the causes of lung malformations and prevention of respiratory distress syndrome and the potential adverse effects of glucocorticoids. Hox genes are involved in the lung branching morphogenesis and maturation of respiratory epithelium, but their expression pattern remains to be defined. OBJECTIVES: We hypothesized that genes involved in lung branching would be downregulated during early development, whereas those involved in maturation would be unchanged or upregulated. METHODS: TaqMan real-time primers and probes were designed for all 39 murine Hox genes, and the murine SP-B gene and transcription profiles of these genes were obtained from whole lungs isolated at e14.5, e16.5, e18.5, e19.5 and postnatal days 1 and 20. RESULTS: Hox genes in clusters A and B, specifically those between paralog groups 3 and 7, were the most represented, with Hoxa4 and Hoxa5 being the most highly transcribed. A wave of reduced transcription in 16 Hox genes, coincident with increased SP-B transcription, was observed with advancing gestation. Consistently high transcription of Hoxa5 from e14.5 to postnatal day 20 may indicate that sustained transcription is required for normal lung maturation. When e15.5 lungs were cultured with dexamethasone, Hoxb6, Hoxb7 and Hoxb8 levels were significantly upregulated, creating the potential for modulation of diverse downstream target genes. CONCLUSIONS: Improved understanding of the genetic processes underlying lung development afforded by our Q-PCR platform may allow development of more specific methods for inducing fetal lung maturation.

Expression of the common heat-shock protein receptor CD91 is increased on monocytes of exposed yet HIV-1-seronegative subjects.

The significantly higher surface expression of the surface heat-shock protein receptor CD91 on monocytes of human immunodeficiency virus type-1 (HIV-1)-infected, long-term nonprogressors suggests that HIV-1 antigen uptake and cross-presentation mediated by CD91 may contribute to host anti-HIV-1 defenses and play a role in protection against HIV-1 infection. To investigate this further, we performed phenotypic analysis to compare CD91 surface expression on CD14+ monocytes derived from a cohort of HIV-1-exposed seronegative (ESN) subjects, their seropositive (SP) partners, and healthy HIV-1-unexposed seronegative (USN) subjects. The median fluorescent intensity (MFI) of CD91 on CD14+ monocytes was significantly higher in ESN compared with SP (P=0.028) or USN (P=0.007), as well as in SP compared with USN subjects (P=0.018). CD91 MFI was not normalized in SP subjects on highly active antiretroviral therapy (HAART) despite sustainable, undetectable plasma viraemia. Data in three SP subjects experiencing viral rebounds following interruption of HAART showed low CD91 MFI comparable with levels in USN subjects. There was a significant positive correlation between CD91 MFI and CD8+ T cell counts in HAART-naïve SP subjects (r=0.7, P=0.015). Increased surface expression of CD91 on CD14+ monocytes is associated with the apparent HIV-1 resistance that is observed in ESN subjects.