Abstract 10636: Chronic Depletion of Glutathione Exacerbates Ventricular Remodeling and Dysfunction in Pressure Overloaded Heart in Mice Lacking the Glutamate-Cysteine Ligase Modifier Subunit
It is suggested that reduced glutathione (GSH) may play a possible role in cardiac remodeling and dysfunction. However, there is no information on the effects of decreasing GSH levels by non-pharmacological modulation of the enzymes directly related to GSH generation. Thus, this study examined the hypothesis that chronic depletion of GSH may exacerbate cardiac remodeling and dysfunction in pressure overloaded heart using mice lacking the modifier subunit of glutamate-cysteine ligase (GCLM), a rate-limiting enzyme for GSH synthesis.
Methods and Results: Pressure overload in heart was created by transverse aortic constriction (TAC). Myocardial GSH content in GCLM knockout (GCLM-/-) mice was 31% of myocardial GSH in GCLM +/+ mice 4 weeks after TAC. GCLM -/- mice exhibited lower survival rate (80% in GCLM-/- vs. 97% in GCLM +/+, p < 0.01), a 66% increase in LV end-diastolic pressure, a 16% and 21% increase in heart and lung weight to body weight ratios, respectively, a 10% increase in LV end-diastolic diameter and a 31% reduction of LV fractional shortening on echocardiography 4 weeks after TAC, as compared with GCLM +/+ mice. GCLM-/- myocardium after TAC had a 52% increase in myocardial fibrosis on Masson’s trichrome staining, compared with GCLM +/+ myocardium in association with greater phosphorylation of Smad3 and higher expression of pro-fibrogenic molecules including connective tissue growth factor, procollagen I and III, and TGF-beta2. SERCA-dependent Ca2+ uptake was decreased in GCLM -/- myocardium by 24% of GCLM +/+ myocardium after TAC partly through the mechanism mediated by reduction in expression and glutathionylation of SERCA2a. Supplementation of GSH ethyl ester attenuated the expression of pro-fibrogenic molecules and Smad3 phosphorylation in response to TGF-beta1 in cultured cardiac fibroblasts and reversed the impairment of [Ca2+]i transients and cell shortening in the cultured cardiomyocytes from GCLM -/- mice.
Conclusions: Chronic depletion of GSH exacerbated ventricular remodeling and dysfunction after pressure overload due to TAC in GCLM -/- mice. GSH depletion increased pro-fibrogenic response to TGF-beta and suppressed SERCA activity, leading to the adverse phenotypic changes in the pressure overloaded heart in GCLM -/- mice.
- © 2012 by American Heart Association, Inc.