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Activation of Both the Calpain and Ubiquitin-Proteasome Systems Contributes to Septic Cardiomyopathy through Dystrophin Loss/Disruption and mTOR Inhibition

View Article: PubMed Central - PubMed

ABSTRACT

Cardiac dysfunction caused by the impairment of myocardial contractility has been recognized as an important factor contributing to the high mortality in sepsis. Calpain activation in the heart takes place in response to increased intracellular calcium influx resulting in proteolysis of structural and contractile proteins with subsequent myocardial dysfunction. The purpose of the present study was to test the hypothesis that increased levels of calpain in the septic heart leads to disruption of structural and contractile proteins and that administration of calpain inhibitor-1 (N-acetyl-leucinyl-leucinyl-norleucinal (ALLN)) after sepsis induced by cecal ligation and puncture prevents cardiac protein degradation. We also tested the hypothesis that calpain plays a role in the modulation of protein synthesis/degradation through the activation of proteasome-dependent proteolysis and inhibition of the mTOR pathway. Severe sepsis significantly increased heart calpain-1 levels and promoted ubiquitin and Pa28β over-expression with a reduction in the mTOR levels. In addition, sepsis reduced the expression of structural proteins dystrophin and β-dystroglycan as well as the contractile proteins actin and myosin. ALLN administration prevented sepsis-induced increases in calpain and ubiquitin levels in the heart, which resulted in decreased of structural and contractile proteins degradation and basal mTOR expression levels were re-established. Our results support the concept that increased calpain concentrations may be part of an important mechanism of sepsis-induced cardiac muscle proteolysis.

No MeSH data available.


Histopathology of myocardial tissue after CLP.Myocytolysis and contraction bands become evident in the SSI group (upper right panel) compared to the SSI+ALLN group (bottom right panel) 24 h after surgery. The SHAM (upper left panel) and SHAM+ALLN (bottom left panel) groups revealed no morphological alterations. Scale bars indicate 50 mm.
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pone.0166839.g001: Histopathology of myocardial tissue after CLP.Myocytolysis and contraction bands become evident in the SSI group (upper right panel) compared to the SSI+ALLN group (bottom right panel) 24 h after surgery. The SHAM (upper left panel) and SHAM+ALLN (bottom left panel) groups revealed no morphological alterations. Scale bars indicate 50 mm.

Mentions: Severe sepsis induced by CLP resulted in intense cellular damage in the myocardium (Fig 1). Cardiac tissue from the SSI group showed widespread and diffuse foci of cardiac myocyte lysis, development of contraction bands necrosis and swollen cytoplasm compared to the hearts of the control animal groups (SHAM and SHAM+ALLN). However, septic mice treated with calpain inhibitor-1 (SSI+ALLN) displayed lower intensity and extended areas of myocytolysis and reduced edema compared with the SSI group at 24 hours after CLP.


Activation of Both the Calpain and Ubiquitin-Proteasome Systems Contributes to Septic Cardiomyopathy through Dystrophin Loss/Disruption and mTOR Inhibition
Histopathology of myocardial tissue after CLP.Myocytolysis and contraction bands become evident in the SSI group (upper right panel) compared to the SSI+ALLN group (bottom right panel) 24 h after surgery. The SHAM (upper left panel) and SHAM+ALLN (bottom left panel) groups revealed no morphological alterations. Scale bars indicate 50 mm.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5120800&req=5

pone.0166839.g001: Histopathology of myocardial tissue after CLP.Myocytolysis and contraction bands become evident in the SSI group (upper right panel) compared to the SSI+ALLN group (bottom right panel) 24 h after surgery. The SHAM (upper left panel) and SHAM+ALLN (bottom left panel) groups revealed no morphological alterations. Scale bars indicate 50 mm.
Mentions: Severe sepsis induced by CLP resulted in intense cellular damage in the myocardium (Fig 1). Cardiac tissue from the SSI group showed widespread and diffuse foci of cardiac myocyte lysis, development of contraction bands necrosis and swollen cytoplasm compared to the hearts of the control animal groups (SHAM and SHAM+ALLN). However, septic mice treated with calpain inhibitor-1 (SSI+ALLN) displayed lower intensity and extended areas of myocytolysis and reduced edema compared with the SSI group at 24 hours after CLP.

View Article: PubMed Central - PubMed

ABSTRACT

Cardiac dysfunction caused by the impairment of myocardial contractility has been recognized as an important factor contributing to the high mortality in sepsis. Calpain activation in the heart takes place in response to increased intracellular calcium influx resulting in proteolysis of structural and contractile proteins with subsequent myocardial dysfunction. The purpose of the present study was to test the hypothesis that increased levels of calpain in the septic heart leads to disruption of structural and contractile proteins and that administration of calpain inhibitor-1 (N-acetyl-leucinyl-leucinyl-norleucinal (ALLN)) after sepsis induced by cecal ligation and puncture prevents cardiac protein degradation. We also tested the hypothesis that calpain plays a role in the modulation of protein synthesis/degradation through the activation of proteasome-dependent proteolysis and inhibition of the mTOR pathway. Severe sepsis significantly increased heart calpain-1 levels and promoted ubiquitin and Pa28β over-expression with a reduction in the mTOR levels. In addition, sepsis reduced the expression of structural proteins dystrophin and β-dystroglycan as well as the contractile proteins actin and myosin. ALLN administration prevented sepsis-induced increases in calpain and ubiquitin levels in the heart, which resulted in decreased of structural and contractile proteins degradation and basal mTOR expression levels were re-established. Our results support the concept that increased calpain concentrations may be part of an important mechanism of sepsis-induced cardiac muscle proteolysis.

No MeSH data available.