Adrenomedullin gene delivery is cardio-protective in a model of chronic nitric oxide deficiency combining pressure overload, oxidative stress and cardiomyocyte hypertrophy
| Autor: | Xuanhui Wang, S. Louise Cosby, Malcolm Campbell, J.A. Philip Earle, Barbara McDermott, David Bell |
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| Rok vydání: | 2010 |
| Předmět: |
medicine.medical_specialty
Physiology Genetic Vectors Vasodilation Cardiomegaly medicine.disease_cause Nitric Oxide Nitric oxide Muscle hypertrophy chemistry.chemical_compound Adrenomedullin Internal medicine medicine Pressure Animals Humans Myocytes Cardiac Pressure overload biology business.industry Superoxide Dismutase Gene Transfer Techniques NADPH Oxidases Rats Disease Models Animal Oxidative Stress Endocrinology NG-Nitroarginine Methyl Ester chemistry biology.protein Systemic administration P22phox business Oxidative stress Atrial Natriuretic Factor |
| Zdroj: | Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology. 26(3) |
| ISSN: | 1421-9778 |
| Popis: | Background/aims: Chronic inhibition of nitric oxide (NO) synthesis is associated with hypertension, myocardial ischemia, oxidative stress and hypertrophy; expression of the vasodilator peptide, adrenomedullin (AM) and its receptors is augmented in cardiomyocytes, indicating that the myocardial AM system may be activated in response to pressure loading and ischemic insult to serve a counter-regulatory, cardio-protective role. The study examined the hypothesis that oxidative stress and hypertrophic remodeling in NO-deficient cardiomyocytes are attenuated by adenoviral vector-mediated delivery of the human adrenomedullin (hAM) gene in vivo. Methods: The NO synthesis inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 15mg · kg-1 · day-1) was given to rats for 4 weeks following systemic administration via the tail vein of a single injection of either adenovirus harbouring hAM cDNA under the control of the cytomegalovirus promoter-enhancer (Ad.CMV-hAM-4F2), or for comparison, adenovirus alone (Ad.Null) or saline. Cardiomyocytes were subsequently isolated for assessment of the influence of each intervention on parameters of oxidative stress and hypertrophic remodelling. Results: Cardiomyocyte expression of the transgene persisted for ≧4 weeks following systemic administration of adenoviral vector. In L-NAME treated rats, relative to Ad.Null or saline administration, Ad.CMV-hAM-4F2 (i) reduced augmented cardiomyocyte membrane protein oxidation and mRNA expression of pro-oxidant (p22phox) and anti-oxidant (SOD-3, GPx) genes; (ii) attenuated increased cardiomyocyte width and mRNA expression of hypertrophic (sk-α-actin) and cardio-endocrine (ANP) genes; (iii) did not attenuate hypertension. Conclusions: Adenoviral vector mediated delivery of hAM resulted in attenuation of myocardial oxidative stress and hypertrophic remodelling in the absence of blood pressure reduction in this model of chronic NO-deficiency. These findings are consistent with a direct cardio-protective action in the myocardium of locally-derived hAM which is not dependant on NO generation. |
| Databáze: | OpenAIRE |
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