Cardiac overexpression of catalase rescues cardiac contractile dysfunction induced by insulin resistance: role of oxidative stress, protein carbonyl formation and insulin sensitivity

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.

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 (ΔFFI) and intracellular Ca²⁺ clearance rate (τ). Reactive oxygen species (ROS) and protein damage were evaluated with dichlorodihydrofluorescein and protein carbonyl formation.

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 τ, and reduced ΔFFI 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 γ (PPARγ), 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 PPARγ.

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.