الفهرس 
قرار لجنة المناقشة والحكمOnly 14 pages are availabe for public view
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Abstract
I) Differential involvement of various sources of reactive oxygen species (ROS)
in thyroxin-induced hemodynamic changes and contractile dysfunction of the
heart and diaphragm muscles in mice.
Thyroid hormones are key regulators of basal metabolic state and oxidative
metabolism. Hyperthyroidism has been reported to cause significant alterations in
hemodynamics, and in cardiac and diaphragm muscle functions, all of which have been
linked to increased oxidative stress. However, the definite source of increased reactive
oxygen species (ROS) in each of these phenotypes is still unknown. The goal of the
current study was to test the hypothesis that thyroxin (T4) may produce distinct
hemodynamic, cardiac, and diaphragm muscle abnormalities by differentially affecting
various sources ofROS. Wild-type and T4 mice with and without 2-week treatments with
allopurinol (xanthine oxidase inhibitor), apocynin (NADPH oxidase inhibitor), L-NIO
(nitric oxide synthase inhibitor), or MitoTEMPO (mitochondria-targeted antioxidant)
were studied. Blood pressure and echocardiography were noninvasively evaluated,
followed by ex vivo assessments of isolated heart and diaphragm muscle functions.
Treatment with L-NIO attenuated the T4-induced hypertension in mice. However,
apocynin improved the left-ventricular (LV) dysfunction without preventing the cardiac
hypertrophy in these mice. Both allopurinol and MitoTEMPO reduced the T4-induced
fatigability of the diaphragm muscles. In conclusion, we show here for the first time that
T4 exerts differential effects on various sources of ROS to induce distinct cardiovascular
and skeletal muscle phenotypes. Additionally, we find that T4-induced LV dysfunction is
independent of cardiac hypertrophy and NADPH oxidase is a key player in this process.
Furthermore, we prove the significance of both xanthine oxidase and mitochondrial ROS
pathways in T4-induced fatigability of diaphragm muscles. Finally, we confirm the
importance of the nitric oxide pathway in T4-induced hypertension.
eywords: Allopurinol; Apocynin; Cardiac muscle; Diaphragm; Free radicals; L-NIO;
MitoTEMPO; Thyroxin