is an important intracellular messenger that regulates myocyte contraction via excitation-contraction (E-C)coupling and gene transcription underlying cardiac hypertrophy. The mechanisms of E-C coupling in immature hearts are believed to be different from those in adult hearts because of the structural immaturity of the sarcoplasmic reticulum (SR) and T-tubules in an immature heart; however, the details of these mechanisms are not completely understood. Neuronal Ca sensor-1 (NCS-1) is an EF-hand Ca 2+-binding protein, which is an important regulator of neuronal functions. Although NCS-1 is expressed in high levels in immature hearts, only little is known about its cardiac functions. In this study, two novel functions of NCS-1 in cardiac tissue was discovered by characterizing the cardiac phenotypes of knockout (Ncs1 -/-) mice. NCS-1 was found to be a regulator of contraction in immature hearts and that of hypertrophy in adult hearts. NCS-1 promotes Ca 2+ release from the inositol trisphosphate receptors (IP3Rs) , followed by Ca 2+ /calmodulin-dependent protein kinase II signaling, which results in a large increase in the SR Ca 2+ content in an immature heart. In addition, NCS-1 expression increased during the early stages of hypertrophy in the adult heart; and phenylephrine-induced cardiac hypertrophy was largely attenuated in Ncs1 -/-hearts. Our results revealed a novel mechanism of E-C coupling in immature hearts and another regulatory mechanism involved in the progression of receptor stimulation-elicited cardiac hypertrophy. 要 旨 心臓の収縮や心肥大・心不全の発症を調節するものとして,細胞内カルシウム (Ca
like ursodeoxycholic acid (UDCA) and tauroursodeoxycholic acid (TUDCA), are cytoprotective and inhibit cell death. The mechanisms associated with these distinct effects are not entirely clear. However, the effect of hydrophilic bile acids seems to be related with the blockage of a series of processes that converge on mitochondrial damage. Bax is a pro-apoptotic protein that belongs to the superfamily of the Bcl-2 proteins and is involved in mitochondrial pore formation. Submicellar concentrations of cytoprotective bile acids have been shown to modulate Bax concentration in mitochondria, suggesting that these molecules may interact directly with the protein. In this study, our objective was to evaluate the affinity of bile acids to recombinant Bax protein, making use of fluorescence spectroscopy (FRET and fluorescence anisotropy), as well as Fluorescence Correlation Spectroscopy (FCS). Our results show that the cytoprotective bile acids UDCA and TUDCA associate with recombinant Bax protein with high affinity, while the cytotoxic bile acid DCA only seems to be able to adsorb to the protein with much lower affinity. Notably, the binding site for UDCA seems to be located in a hydrophobic pocket of the protein. This interaction could be responsible for the disruption of Bax translocation to the mitochondrial outer membrane in the presence of UDCA and/or TUDCA. Supported from FCT/Portugal (Projects PTDC/QUI-BIQ/119494/
Smoking is known as a risk factor for cardiovascular diseases. Recently, the use of heated cigarettes, which are expected to be a less toxic, has increased in Japan. However, little is known about their direct effects on cardiomyocytes. In the present study, we compared the effects of heated and a combustible cigarette smoke extracts (CSEs) on the cell viability, contractile function and intracellular Ca 2+ dynamics of freshly isolated or cultured rat cardiomyocytes. We used Ploom X (PX) and IQOS (IQ) as heated CSEs, and 1R6F (RF) as a combustible CSE. The cell viability (MTS) assay using cultured myocytes showed that the order of toxic effects was RF>IQ>PX. Functional analysis using the Cell Motion Imaging System showed that all types of 1% CSE reduced cardiomyocyte contractility with their impairing activity RF≒IQ>PX. Intracellular Ca 2+ dynamics analysis showed that all types of 1% CSE decreased the Ca 2+ -transient amplitude, which may be the mechanism of reduced contractility. In addition, RF treatment induce Ca 2+ leakage (possibly from sarcoplasmic reticulum), which may be the cause of the increased diastolic Ca 2+ levels. Furthermore, the spontaneous beating rate of cultured cardiomyocytes was markedly reduced by RF. Taken together, these results indicate that heated cigarette extracts are also toxic to cell viability and contraction of cardiomyocytes. In addition, each CSE had different effects on intracellular Ca 2+ dynamics, suggesting that mechanism of action is different.
Mechanism of excitation-contraction (EC) coupling in immature hearts are considered to be different from those in the adults because of the structural immaturity of the sarcoplasmic reticulum (SR), an intracellular Ca 2+ store, and the different expression of Ca 2+ -regulatory proteins. However, the detailed molecular mechanism is not completely understood. In the present study, we identified neuronal Ca 2+ sensor-1 (NCS-1), an EF-hand Ca 2+ binding protein that is important for neuronal functions, also functions as a novel regulator of EC coupling in young hearts. We found that NCS-1 is highly expressed in immature hearts, and its deletion decreased their contractile functions. NCS-1 enhances Ca 2+ signals mainly by promoting the IP 3 receptor functions, followed by CaMKII signaling, which results in a large increase in the SR Ca 2+ content that enhances SR-dependent EC coupling. In addition, NCS-1 expression increases in the early stages of hypertrophy and promotes progression of hypertrophy at least in part through IP 3 Rdependent elevation of nuclear Ca 2+ signaling. Our results reveal a previously unrecognized mechanism of EC coupling in young heart and the progression of cardiac hypertrophy. We propose that the proteins involved in NCS-1mediating Ca 2+ signaling can be novel therapeutic targets for cardiac diseases in immature hearts.
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