Cardiac overexpression of antioxidant catalase attenuates aging-induced cardiomyocyte relaxation dysfunction

Abstract

Catalase, an enzyme which detoxifies H 2 O 2 , may interfere with cardiac aging. To test this hypothesis, contractile and intracellular Ca 2+ properties were evaluated in cardiomyocytes from young (3-4 mo) and old (26-28 mo) FVB and transgenic mice with cardiac overexpression of catalase. Contractile indices analyzed included peak shortening (PS), time-to-90% PS (TPS 90 ), time-to-90% relengthening (TR 90 ), half-width duration (HWD), maximal velocity of shortening/relengthening (± dL/dt) and intracellular Ca 2+ levels or decay rate. Levels of advanced glycation endproduct (AGE), Na + /Ca 2+ exchanger (NCX), sarco(endo)plasmic reticulum Ca 2+ -ATPase (SERCA2a), phospholamban (PLB), myosin heavy chain (MHC), membrane Ca 2+ and K + channels were measured by western blot. Catalase transgene prolonged survival while did not alter myocyte function by itself. Aging depressed ± dL/dt, prolonged HWD, TR 90 and intracellular Ca 2+ decay without affecting other indices in FVB myocytes. Aged FVB myocytes exhibited a stepper decline in PS in response to elevated stimulus or a dampened rise in PS in response to elevated extracellular Ca 2+ levels. Interestingly, aging-induced defects were nullified or significantly attenuated by catalase. AGE level was elevated by 5-fold in aged FVB compared with young FVB mice, which was reduced by catalase. Expression of SERCA2a, NCX and Kv 1.2 K + channel was significantly reduced although levels of PLB, L-type Ca 2+ channel dihydropyridine receptor and β-MHC isozyme remained unchanged in aged FVB hearts. Catalase restored NCX and Kv 1.2 K + channel but not SERCA2a level in aged mice. In summary, our data suggested that catalase protects cardiomyocytes from aginginduced contractile defect possibly via improved intracellular Ca 2+ handling.

NADPH oxidase-derived superoxide impairs calcium transients and contraction in aged murine ventricular myocytes

“…However, previously we could not find any age-dependent change in cardiac SERCA2 expression in C57BL/6 mice . Additionally, we show that aging had no effect on the expression of DHP receptor α subunit, RyR2, phospholamban, calsequestrin and NCX1 confirming previous analyses by other groups (Li et al, 2007;Xu and Narayanan, 1998). In conclusion, it seems very unlikely that in the mouse strain C57BL/6 altered calcium handling protein expression accounts for the contractile dysfunction of aged ventricular…”

“…Similarly, in aged rat hearts reduced SERCA2 expression and activity was demonstrated (Buttrick et al, 1991;Froehlich et al, 1978;Lompre et al, 1991). Li et al (2007) recently reported reduced SERCA2 expression and activity in aged hearts of FVB mice, whereas we previously showed diastolic dysfunction in aged ventricular myocytes of C57BL/6 mice without changes in protein expression of SERCA2 . Therefore, depending on the strain used calcium handling may be additionally modulated by posttranslational mechanisms in aged rodent ventricular myocytes.…”

“…Similarly, reduced cardiac expression of SERCA2 was demonstrated for aged rats and FVB mice, respectively (Buttrick et al, 1991;Lompre et al, 1991;Li et al, 2007). However, previously we could not find any age-dependent change in cardiac SERCA2 expression in C57BL/6 mice .…”

“…Recently, it was reported that lifelong constitutive overexpression of antioxidative enzymes prevents age-dependent diastolic dysfunction in murine ventricular myocytes providing further evidence for oxidative stress to be involved (Dai et al, 2009;Ren et al, 2007;Yang et al, 2006).…”

Altered left ventricular performance in aging physically active mice with an ankle sprain injury

“…The authors are unaware of any other investigations into end of life LV alpha or beta MHC content with a longitudinal model in exercising mice that would allow for any comparisons to our findings. Additionally, it should be noted that past literature acknowledges the difficulty in comparing cardiac MHC, along with other myocardial parameters, with senescent animals and cautions investigators to this issue with regard to animal species, strain, gender, and experimental condition (Ren et al 2007). …”