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    Mechanism of age-related cardiac dysfunction: Role of iNOS

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    Author
    Yang, Bo
    Issue Date
    2003
    Keywords
    Health Sciences, Pharmacology.
    Health Sciences, Public Health.
    Advisor
    French, Edward D.
    
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    Publisher
    The University of Arizona.
    Rights
    Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
    Abstract
    It is well documented that in the human free of pathological change, there is cardiac diastolic dysfunction with decreased reserved systolic function. Inducible nitric oxide synthase (iNOS) expressed in cardiac myocytes is related to heart failure of various etiologies. We hypothesized that the high levels of nitric oxide (NO) produced by iNOS over-expressed in the myocardium caused age-related cardiac dysfunction by affecting calcium cycling proteins. To test our hypothesis, first, we validated the volumetric measurement of the conductance catheter system (CCS) in mice. The heart function characterized by CCS decreased in aged mice (16-month-old, n = 9) compared to Young mice (6-month-old, n = 9). The left ventricular (LV) dysfunction in aged WT mice was reversed by iNOS specific inhibitors, aminoguanidine (AMG, 10 mg/Kg, i.v. or infusion, n = 15) and S-methyl-isothiourea (MITU, 3 mg/Kg, i.v. n = 7) separately and worsened by substrate L-arginine (10 mg/Kg, i.v. n = 7). All three drugs had no effects on young WT mice or old (16-month-old) iNOS knockout (KO) mice. Cardiac iNOS mRNA and protein expression were identified with northern blot, western blot and immunohistochemistry singularly in old WT mice and not in young WT mice. The NOx and cGMP levels were significantly higher only in the old WT mice (n = 6) compared to young WT mice and cGMP levels decreased to normal with AMG administration in the old WT mice. Northern blot showed the expression of ryanodine receptor, sarco/endoplasmic reticulum (SERCA 2a) did not change in the aging process. However western blots showed that total phospholamban (PLB), phosphorylated PLB (p < 0.05) and more importantly the ratio of phosphorylated PLB to total PLB significantly decreased in aged mice (p < 0.01). AMG (10 mg/kg bolus iv) significantly improved diastolic function only in the old WT mice with decreased tau and increased dP/dtmin, but had no effects on both young or old PLB knockout mice. Taken together, we concluded that iNOS overexpression was one of the mechanisms leading to age-related cardiac dysfunction by affecting phosphorylation of PLB via iNOS/NO/cGMP pathways and inhibition of iNOS could reverse the age-related cardiac dysfunction.
    Type
    text
    Dissertation-Reproduction (electronic)
    Degree Name
    Ph.D.
    Degree Level
    doctoral
    Degree Program
    Graduate College
    Pharmacology & Toxicology
    Degree Grantor
    University of Arizona
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