Cardiac overexpression of catalase rescues cardiac contractile dysfunction induced by insulin resistance: Role of oxidative stress, protein carbonyl formation and insulin sensitivity.
OBJECTIVE
Insulin resistance leads to oxidative stress and cardiac dysfunction. This study examined the impact of catalase on insulin-resistance-induced cardiac dysfunction, oxidative damage and insulin sensitivity.


METHODS
Insulin resistance was initiated in FVB and catalase-transgenic mice by 12 weeks of sucrose feeding. Contractile and intracellular Ca2+ properties were evaluated in cardiomyocytes including peak shortening (PS), time-to-PS (TPS), time-to-90% relengthening (TR90), half-width duration (HWD), maximal velocity of shortening/relengthening (+/-dL/dt), fura-fluorescence intensity change (DeltaFFI) and intracellular Ca2+ clearance rate (tau). Reactive oxygen species (ROS) and protein damage were evaluated with dichlorodihydrofluorescein and protein carbonyl formation.


RESULTS
Sucrose-fed mice displayed hyperinsulinaemia, impaired glucose tolerance and normal body weight. Myocytes from FVB sucrose-fed mice exhibited depressed PS and +/-dL/dt, prolonged TR90 and tau, and reduced DeltaFFI associated with normal TPS and HWD compared with those from starch-fed control mice. ROS and protein carbonyl formation were elevated in FVB sucrose-fed mice. Insulin sensitivity was reduced, evidenced by impaired insulin-stimulated 2-deoxy-D: -[3H]glucose uptake. Western blot analysis indicated that sucrose feeding: (1) inhibited insulin-stimulated phosphorylation of insulin receptor and Akt; (2) enhanced protein-tyrosine phosphatase 1B (PTP1B) expression; and (3) suppressed endothelial nitric oxide synthase (eNOS) and Na+-Ca2+ exchanger expression without affecting peroxisome proliferator-activated receptor gamma (PPARgamma), sarco(endo)plasmic reticulum Ca2+-ATPase isozyme 2a and phospholamban. Catalase ablated insulin-resistance-induced mechanical dysfunction, ROS production and protein damage, and reduced eNOS, but not insulin insensitivity. Catalase itself decreased resting FFI and enhanced expression of PTP1B and PPARgamma.


CONCLUSIONS
These data indicate that catalase rescues insulin-resistance-induced cardiac dysfunction related to ROS production and protein oxidation but probably does not improve insulin sensitivity.
Division of Pharmaceutical Sciences and Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, 1000 E. University Avenue, Department 3375, Laramie, WY 82071, USA.
F
F
Dong
C X
CX
Fang
X
X
Yang
X
X
Zhang
F L
FL
Lopez
J
J
Ren
D000818:Animals; D001692:Biological Transport; D002374:Catalase / Q000235:genetics*; D004040:Dietary Carbohydrates; D005260:Female; D005947:Glucose / Q000378:metabolism; D006352:Heart Ventricles / Q000166:cytology; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D032342:Muscle Cells / Q000502:physiology; D009200:Myocardial Contraction / Q000502:physiology*; D009206:Myocardium / Q000201:enzymology*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D016276:Ventricular Function
D004040:Dietary Carbohydrates; D017382:Reactive Oxygen Species; D002374:Catalase; D005947:Glucose