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Regulation of Cardiac Remodeling by Cardiac Na + /K + -ATPase Isoforms

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ABSTRACT

Cardiac remodeling occurs after cardiac pressure/volume overload or myocardial injury during the development of heart failure and is a determinant of heart failure. Preventing or reversing remodeling is a goal of heart failure therapy. Human cardiomyocyte Na+/K+-ATPase has multiple α isoforms (1–3). The expression of the α subunit of the Na+/K+-ATPase is often altered in hypertrophic and failing hearts. The mechanisms are unclear. There are limited data from human cardiomyocytes. Abundant evidences from rodents show that Na+/K+-ATPase regulates cardiac contractility, cell signaling, hypertrophy and fibrosis. The α1 isoform of the Na+/K+-ATPase is the ubiquitous isoform and possesses both pumping and signaling functions. The α2 isoform of the Na+/K+-ATPase regulates intracellular Ca2+ signaling, contractility and pathological hypertrophy. The α3 isoform of the Na+/K+-ATPase may also be a target for cardiac hypertrophy. Restoration of cardiac Na+/K+-ATPase expression may be an effective approach for prevention of cardiac remodeling. In this article, we will overview: (1) the distribution and function of isoform specific Na+/K+-ATPase in the cardiomyocytes. (2) the role of cardiac Na+/K+-ATPase in the regulation of cell signaling, contractility, cardiac hypertrophy and fibrosis in vitro and in vivo. Selective targeting of cardiac Na+/K+-ATPase isoform may offer a new target for the prevention of cardiac remodeling.

No MeSH data available.


Schematic diagram of Na+/K+-ATPase pumping and signaling functions in cardiomyocytes (Liu et al., 2006, 2007; Wu et al., 2015). Inhibited pump alters local [Na+]i and induces myocytes contractility; Major effect of ouabain signaling is Src/Ras/ROS/ERK cascade in α1/ α3 neonatal cardiomyocytes; Major effect of ouabain signaling is PI3Kα /Akt pathway in α1/ α2 adult cardiomyocytes.
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Figure 1: Schematic diagram of Na+/K+-ATPase pumping and signaling functions in cardiomyocytes (Liu et al., 2006, 2007; Wu et al., 2015). Inhibited pump alters local [Na+]i and induces myocytes contractility; Major effect of ouabain signaling is Src/Ras/ROS/ERK cascade in α1/ α3 neonatal cardiomyocytes; Major effect of ouabain signaling is PI3Kα /Akt pathway in α1/ α2 adult cardiomyocytes.

Mentions: Besides its ion pumping function, the Na+/K+-ATPase also serves as a scaffold protein interacting with neighboring proteins and facilitates multiple cell signaling events. As shown in Figure 1, Na+/K+-ATPase signaling mainly has two parallel pathways, one is the EGFR/Src/ERK pathway and another is the phosphoinositide 3-kinase (PI3K) α/Akt/β-GSK/mTOR pathway. To be sure there is some debate regarding the nature of the interaction between the Na+/K+-ATPase and Src (Weigand et al., 2012; Clifford and Kaplan, 2013; Yosef et al., 2016). Ouabain indeed does activate Src in myocytes (Haas et al., 2000; Mohammadi et al., 2001, 2003; Xie and Askari, 2002; Liu et al., 2003, 2004) and several lines of evidence support the finding that the Na+/K+-ATPase and Src do interact and induced by ouabain or high salt by immunoprecipitation assay in cardiomyocytes, breast cancer cells, and primary pig proximal tubular cells and LLC-PK1 cells (Mohammadi et al., 2003; Kometiani et al., 2005; Liu et al., 2011; Yan et al., 2013). However, the mechanisms of the interaction between the Na+/K+-ATPase and Src are unclear. The mechanistic analysis on living cells are required to clarify the complicated network in cells. Thus, some of the conflicting results regarding the interaction between the Na+/K+-ATPase and Src may be related not only to cell specificity and specific in vitro conditions with detergent-treated membrane purified sodium pump.


Regulation of Cardiac Remodeling by Cardiac Na + /K + -ATPase Isoforms
Schematic diagram of Na+/K+-ATPase pumping and signaling functions in cardiomyocytes (Liu et al., 2006, 2007; Wu et al., 2015). Inhibited pump alters local [Na+]i and induces myocytes contractility; Major effect of ouabain signaling is Src/Ras/ROS/ERK cascade in α1/ α3 neonatal cardiomyocytes; Major effect of ouabain signaling is PI3Kα /Akt pathway in α1/ α2 adult cardiomyocytes.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5016610&req=5

Figure 1: Schematic diagram of Na+/K+-ATPase pumping and signaling functions in cardiomyocytes (Liu et al., 2006, 2007; Wu et al., 2015). Inhibited pump alters local [Na+]i and induces myocytes contractility; Major effect of ouabain signaling is Src/Ras/ROS/ERK cascade in α1/ α3 neonatal cardiomyocytes; Major effect of ouabain signaling is PI3Kα /Akt pathway in α1/ α2 adult cardiomyocytes.
Mentions: Besides its ion pumping function, the Na+/K+-ATPase also serves as a scaffold protein interacting with neighboring proteins and facilitates multiple cell signaling events. As shown in Figure 1, Na+/K+-ATPase signaling mainly has two parallel pathways, one is the EGFR/Src/ERK pathway and another is the phosphoinositide 3-kinase (PI3K) α/Akt/β-GSK/mTOR pathway. To be sure there is some debate regarding the nature of the interaction between the Na+/K+-ATPase and Src (Weigand et al., 2012; Clifford and Kaplan, 2013; Yosef et al., 2016). Ouabain indeed does activate Src in myocytes (Haas et al., 2000; Mohammadi et al., 2001, 2003; Xie and Askari, 2002; Liu et al., 2003, 2004) and several lines of evidence support the finding that the Na+/K+-ATPase and Src do interact and induced by ouabain or high salt by immunoprecipitation assay in cardiomyocytes, breast cancer cells, and primary pig proximal tubular cells and LLC-PK1 cells (Mohammadi et al., 2003; Kometiani et al., 2005; Liu et al., 2011; Yan et al., 2013). However, the mechanisms of the interaction between the Na+/K+-ATPase and Src are unclear. The mechanistic analysis on living cells are required to clarify the complicated network in cells. Thus, some of the conflicting results regarding the interaction between the Na+/K+-ATPase and Src may be related not only to cell specificity and specific in vitro conditions with detergent-treated membrane purified sodium pump.

View Article: PubMed Central - PubMed

ABSTRACT

Cardiac remodeling occurs after cardiac pressure/volume overload or myocardial injury during the development of heart failure and is a determinant of heart failure. Preventing or reversing remodeling is a goal of heart failure therapy. Human cardiomyocyte Na+/K+-ATPase has multiple α isoforms (1–3). The expression of the α subunit of the Na+/K+-ATPase is often altered in hypertrophic and failing hearts. The mechanisms are unclear. There are limited data from human cardiomyocytes. Abundant evidences from rodents show that Na+/K+-ATPase regulates cardiac contractility, cell signaling, hypertrophy and fibrosis. The α1 isoform of the Na+/K+-ATPase is the ubiquitous isoform and possesses both pumping and signaling functions. The α2 isoform of the Na+/K+-ATPase regulates intracellular Ca2+ signaling, contractility and pathological hypertrophy. The α3 isoform of the Na+/K+-ATPase may also be a target for cardiac hypertrophy. Restoration of cardiac Na+/K+-ATPase expression may be an effective approach for prevention of cardiac remodeling. In this article, we will overview: (1) the distribution and function of isoform specific Na+/K+-ATPase in the cardiomyocytes. (2) the role of cardiac Na+/K+-ATPase in the regulation of cell signaling, contractility, cardiac hypertrophy and fibrosis in vitro and in vivo. Selective targeting of cardiac Na+/K+-ATPase isoform may offer a new target for the prevention of cardiac remodeling.

No MeSH data available.