In:
American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 302, No. 10 ( 2012-05-15), p. H2008-H2017
Abstract:
Calsequestrin (CSQ) is a Ca 2+ storage protein that interacts with triadin (TRN), the ryanodine receptor (RyR), and junctin (JUN) to form a macromolecular tetrameric Ca 2+ signaling complex in the cardiac junctional sarcoplasmic reticulum (SR). Heart-specific overexpression of CSQ in transgenic mice (TG CSQ ) was associated with heart failure, attenuation of SR Ca 2+ release, and downregulation of associated junctional SR proteins, e.g., TRN. Hence, we tested whether co-overexpression of CSQ and TRN in mouse hearts (TG CxT ) could be beneficial for impaired intracellular Ca 2+ signaling and contractile function. Indeed, the depressed intracellular Ca 2+ concentration ([Ca] i ) peak amplitude in TG CSQ was normalized by co-overexpression in TG CxT myocytes. This effect was associated with changes in the expression of cardiac Ca 2+ regulatory proteins. For example, the protein level of the L-type Ca 2+ channel Ca v 1.2 was higher in TG CxT compared with TG CSQ . Sarco(endo)plasmic reticulum Ca 2+ -ATPase 2a (SERCA2a) expression was reduced in TG CxT compared with TG CSQ , whereas JUN expression and [ 3 H]ryanodine binding were lower in both TG CxT and TG CSQ compared with wild-type hearts. As a result of these expressional changes, the SR Ca 2+ load was higher in both TG CxT and TG CSQ myocytes. In contrast to the improved cellular Ca 2+ , transient co-overexpression of CSQ and TRN resulted in a reduced survival rate, an increased cardiac fibrosis, and a decreased basal contractility in catheterized mice, working heart preparations, and isolated myocytes. Echocardiographic and hemodynamic measurements revealed a depressed cardiac performance after isoproterenol application in TG CxT compared with TG CSQ . Our results suggest that co-overexpression of CSQ and TRN led to a normalization of the SR Ca 2+ release compared with TG CSQ mice but a depressed contractile function and survival rate probably due to cardiac fibrosis, a lower SERCA2a expression, and a blunted response to β-adrenergic stimulation. Thus the TRN-to-CSQ ratio is a critical modulator of the SR Ca 2+ signaling.
Type of Medium:
Online Resource
ISSN:
0363-6135
,
1522-1539
DOI:
10.1152/ajpheart.00457.2011
Language:
English
Publisher:
American Physiological Society
Publication Date:
2012
detail.hit.zdb_id:
1477308-9
SSG:
12
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