Abstract 16302: Early Alterations in Nuclear Ca2+ Handling - Key Role in Heart Failure Progression?
Nucleoplasmic Ca concentration ([Ca]nuc) in cardiac myocytes (CMs) modulates transcription and its alteration is involved in remodeling processes. We thus characterized changes of nuclear Ca handling at the early and late stage of hypertrophy in mouse model of pressure overload and in failing human hearts. Ventricular CMs were isolated 1 and 7 weeks after transverse aortic constriction (TAC) in mice as well as from 8 donor and 4 failing human hearts. Subcellular [Ca] transients (CaTs) were recorded in electrically stimulated CMs loaded with Fluo-4/AM. Phosphorylation levels of CaMKIIδ were quantified by Western blots. Expression patterns of Ca-regulating proteins were visualized by immunocytostaining. In the early stage of hypertrophy, i.e. 1 week after TAC intervention in mice and in moderately failing human hearts (55%>EF>35%), significant changes in kinetics and amplitude of CaTs were found selectively in the nucleus. Slower decay of nucleoplasmic CaTs led to a much higher build-up of diastolic [Ca]nuc as compared to healthy controls when diastole was shortened by increase in stimulation frequency from 0.5 to 5 Hz (Figure). 7 weeks after TAC, as well as in severely failing human hearts (EF≤35%), similar changes of CaTs also occurred in the cytoplasm. High pacing frequency caused significantly higher phosphorylation of CaMKIIδ in CMs from hypertrophic hearts compared to healthy controls. Immunostaining of Ca regulatory proteins showed that CMs from failing mouse and human hearts contain less RyRs and more IP3Rs in perinuclear regions compared to controls, suggesting an increase in local IP3-induced Ca fluxes in the regions surrounding the nucleus. In conclusion, we found that the higher build-up of basal [Ca]nuc observed in CMs from hypertrophic hearts within a range of stimulation frequencies, may - together with the accumulation of IP3Rs in the perinuclear region - alter both, local and global nuclear Ca handling and induce dysregulation of gene transcription.
- © 2012 by American Heart Association, Inc.