Metallothionein suppresses angiotensin II-induced nicotinamide adenine dinucleotide phosphate oxidase activation, nitrosative stress, apoptosis, and pathological remodeling in the diabetic heart.
OBJECTIVE
We evaluated metallothionein (MT)-mediated cardioprotection from angiotensin II (Ang II)-induced pathologic remodeling with and without underlying diabetes.


BACKGROUND
Cardiac-specific metallothionein-overexpressing transgenic (MT-TG) mice are resistant to diabetic cardiomyopathy largely because of the antiapoptotic and antioxidant effects of MT.


METHODS
The acute and chronic cardiac effects of Ang II were examined in MT-TG and wild-type (WT) mice, and the signaling pathways of Ang II-induced cardiac cell death were examined in neonatal mouse cardiomyocytes.


RESULTS
Acute Ang II administration to WT mice or neonatal cardiomyocytes increased cardiac apoptosis, nitrosative damage, and membrane translocation of the nicotinamide adenine dinucleotide phosphate oxidase (NOX) isoform p47(phox). These effects were abrogated in MT-TG mice, MT-TG cardiomyocytes, and WT cardiomyocytes pre-incubated with peroxynitrite or superoxide scavengers and NOX inhibitors, suggesting a critical role for NOX activation in Ang II-mediated apoptosis. Prolonged administration of subpressor doses of Ang II (0.5 mg/kg every other day for 2 weeks) also induced apoptosis and nitrosative damage in both diabetic and nondiabetic WT hearts, but not in diabetic and nondiabetic MT-TG hearts. Long-term follow-up (1 to 6 months) of both WT and MT-TG mice after discontinuing Ang II administration revealed progressive myocardial fibrosis, hypertrophy, and dysfunction in WT mice but not in MT-TG mice.


CONCLUSIONS
Metallothionein suppresses Ang II-induced NOX-dependent nitrosative damage and cell death in both nondiabetic and diabetic hearts early in the time course of injury and prevents the late development of Ang II-induced cardiomyopathy.
Zhou
Guihua
G
Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky, USA.
Li
Xiaokun
X
Hein
David W
DW
Xiang
Xilin
X
Marshall
James P
JP
Prabhu
Sumanth D
SD
Cai
Lu
L
D000804:Angiotensin II / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D009202:Cardiomyopathies / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control; D005355:Fibrosis; D006984:Hypertrophy; D008668:Metallothionein / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000473:pathology*; D032383:Myocytes, Cardiac; D009249:NADP / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D020257:Ventricular Remodeling / Q000502:physiology*
D000804:Angiotensin II; D009249:NADP; D008668:Metallothionein