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Reiter, C.
Cardiac ryanodine receptor and regulation of nuclear Ca(2+) in a mouse model of heart failure
Humanmedizin; [ Diplomarbeit ] ; 2015. pp. [OPEN ACCESS]
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Authors Med Uni Graz:
Advisor:: Holzer Senka; Sedej Simon
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Abstract:: Early alterations of nuclear Ca2+ handling are associated with myocardial remodeling (e.g hypertrophy) and the development of heart failure. Defective intracellular Ca2+ release channel (ryanodine receptor type 2, RyR2) function disturbs cytosolic Ca2+ homeostasis and promotes myocardial remodeling. However, it remains elusive whether RyR2 dysfunction has an impact on the regulation of nuclear Ca2+ handling in response to pressure overload. RyR2R4496C+/- (gain-of-function mutation) adult mice and their wild type (WT) littermates underwent Sham surgery (control) or transverse aortic constriction (TAC) to induce pressure overload. Ventricular cardiomyocytes were isolated seven days after surgery and loaded with 8 µmol/L Fluo-4/AM (Ca2+-sensitive dye). Amplitudes and kinetics of Ca2+ transients in the cytoplasm and nucleus were monitored in electrically field-stimulated cardiac myocytes (at 1Hz) using confocal microscopy (line-scan mode). Cardiomyocytes from Sham-operated mice showed similar cytoplasmic and nucleoplasmic Ca2+ transient amplitudes and kinetics. However, after 1 week of TAC the peak cytoplasmic Ca2+ transient amplitude was increased in WT cells, but nucleoplasmic Ca2+ transient amplitude and kinetics were normal. In contrast, RyR2R4496C+/--TAC cells had significantly smaller cytoplasmic and nucleoplasmic Ca2+ transient amplitudes as well as slower kinetics (time-to-peak and decay time) of nucleoplasmic Ca2+ transients. The combination of acquired and congenital RyR2 dysfunction prolongs nuclear Ca2+ transients and reduces their amplitude in RyR2R4496C+/- hearts after pressure overload. These results suggest that RyR2-mediated Ca2+ changes in the nucleus may underlie altered gene transcription and promote cardiac remodeling.