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.
Highlights
The slow force response (SFR) to myocardial stretch is a second increase in developed force that occurs just after the Frank–Starling mechanism takes place
Our interest in deciphering the subcellular basis of this important mechanism is beyond its physiological role, given that crucial signals leading to the SFR play critical roles in the development of pathological cardiac hypertrophy [19, 20]
The long journey toward cardiac hypertrophy and failure begins with one step, which may well be the autocrine intracellular signaling pathway triggered by myocardial stretch [3]
Summary
The slow force response (SFR) to myocardial stretch is a second increase in developed force that occurs just after the Frank–Starling mechanism takes place. It is well-known that an augmented calcium transient amplitude underlies its development [1, 2] but the exact genesis of this increase is still a matter of debate. We demonstrated that an increased production of reactive oxygen species (ROS) is critical in the chain of events leading to SFR generation [4, 5]. Suppression of ROS production blunted the SFR as shown by us [4] and others [6]. We provided evidence about mitochondrial origin of ROS but induced by a small amount of NADPH oxidase-derived ROS [4], which clearly resembles the so-called “ROS-induced ROS-release” phenomenon [7,8,9]
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