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. 2021 Feb 26:8:622583.
doi: 10.3389/fcvm.2021.622583. eCollection 2021.

Thioredoxin 1 (TRX1) Overexpression Cancels the Slow Force Response (SFR) Development

Affiliations

Thioredoxin 1 (TRX1) Overexpression Cancels the Slow Force Response (SFR) Development

Maite R Zavala et al. Front Cardiovasc Med. .

Abstract

The stretch of cardiac muscle increases developed force in two phases. The first phase occurs immediately after stretch and is the expression of the Frank-Starling mechanism, while the second one or slow force response (SFR) occurs gradually and is due to an increase in the calcium transient amplitude. An important step in the chain of events leading to the SFR generation is the increased production of reactive oxygen species (ROS) leading to redox sensitive ERK1/2, p90RSK, and NHE1 phosphorylation/activation. Conversely, suppression of ROS production blunts the SFR. The purpose of this study was to explore whether overexpression of the ubiquitously expressed antioxidant molecule thioredoxin-1 (TRX1) affects the SFR development and NHE1 phosphorylation. We did not detect any change in basal phopho-ERK1/2, phopho-p90RSK, and NHE1 expression in mice with TRX1 overexpression compared to wild type (WT). Isolated papillary muscles from WT or TRX1-overexpressing mice were stretched from 92 to 98% of its maximal length. A prominent SFR was observed in WT mice that was completely canceled in TRX1 animals. Interestingly, myocardial stretch induced a significant increase in NHE1 phosphorylation in WT mice that was not detected in TRX1-overexpressing mice. These novel results suggest that magnification of cardiac antioxidant defense power by overexpression of TRX1 precludes NHE1 phosphorylation/activation after stretch, consequently blunting the SFR development.

Keywords: NHE1; SFR; TRX1; antioxidant; cardiac hypertrophy.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
SFR development of isolated papillary muscles from WT and TRX1-overexpressing mice. (A) Original force record of an isolated papillary muscle from a WT mouse that was suddenly stretched from 92 to 98% of Lmax. The characteristic two-phase increase in force that follows myocardial stretch can be observed. Individual traces corresponding to developed force indicated in the upper panel with “a” (before stretch), “b” (immediately after stretch), and “c” (10 min after stretch) are shown in the bottom panel. (B) Same as A, but in a papillary muscle from a TRX1-overexpressing mouse where the SFR development was completely canceled. (C) Averaged SFR results after 10 min of stretch from both experimental groups, expressed as percent of the initial rapid phase. *Indicates p < 0.05 vs. WT.
Figure 2
Figure 2
NHE1 phosphorylation after stretch. Myocardial stretch promoted a significant increase in NHE1 phosphorylation in WT mice (“St-WT”) compared to non-stretched controls (“C-WT”), as shown in the original immunoblot (upper panel) and in the averaged results of the lower left panel. Interestingly, the stretch of muscles overexpressing TRX1 (“St-TRX1”) did not show significant changes in NHE1 phosphorylation compared to its corresponding non-stretched controls (“C-TRX1”), as shown in the immunoblot (upper panel), and in the averaged results (lower right panel). *Indicates p < 0.05 vs. C-WT.
Figure 3
Figure 3
ERK1/2, p90RSK phosphorylation, and NHE1 expression. Basal ERK1/2 (A) and p90RSK (B) phosphorylation, as well as NHE1 expression (C) were similar in both experimental groups. Original blots (top) and averaged data (bottom).

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