Background:
Cardiac hypertrophy involves marked wall thickening or chamber enlargement.
If sustained, this condition will lead to dysfunctional mitochondria and oxidative stress. Mitochondria
have ATP-sensitive K+ channels (mitoKATP) in the inner membrane that modulate the redox
status of the cell.
Objective:
We investigated the in vivo effects of mitoKATP opening on oxidative stress in isoproterenol-
induced cardiac hypertrophy.
Methods:
Cardiac hypertrophy was induced in Swiss mice treated intraperitoneally with isoproterenol
(ISO - 30 mg/kg/day) for 8 days. From day 4, diazoxide (DZX - 5 mg/kg/day) was used in order to open
mitoKATP (a clinically relevant therapy scheme) and 5-hydroxydecanoate (5HD - 5 mg/kg/day) or
glibenclamide (GLI - 3 mg/kg/day) were used as mitoKATP blockers.
Results:
Isoproterenol-treated mice had elevated heart weight/tibia length ratios (HW/TL). Additionally,
hypertrophic hearts had elevated levels of carbonylated proteins and Thiobarbituric Acid Reactive
Substances (TBARS), markers of protein and lipid oxidation. In contrast, mitoKATP opening with
DZX avoided ISO effects on gross hypertrophic markers (HW/TL), carbonylated proteins and TBARS,
in a manner reversed by 5HD and GLI. Moreover, DZX improved mitochondrial superoxide dismutase
activity. This effect was also blocked by 5HD and GLI. Additionally, ex vivo treatment of isoproterenol-
induced hypertrophic cardiac tissue with DZX decreased H2O2 production in a manner sensitive to
5HD, indicating that this drug also acutely avoids oxidative stress.
Conclusion:
Our results suggest that diazoxide blocks oxidative stress and reverses cardiac hypertrophy.
This pharmacological intervention could be a potential therapeutic strategy to prevent oxidative
stress associated with cardiac hypertrophy.
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