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Inhibition of the mTOR Pathway Exerts Cardioprotective Effects Partly through Autophagy in CLP Rats.

Abstract：

Background:Sepsis-induced myocardial dysfunction is a severe clinical problem. Recent studies have indicated that autophagy and myocardial energy depletion play a major role in myocardial dysfunction during sepsis, a mechanistic target of rapamycin (mTOR) as a master sensor of energy status and autophagy mediator; however, there are little data describing its role during sepsis in the heart. Methods:Cecal ligation and puncture (CLP) or sham operation (SHAM) was performed in rats. After treatment, pathological changes were determined by H&E staining, cardiac functions by echocardiography, the distribution of microtubule-associated protein light chain 3 (LC-3) type II and hypoxia-inducible factor 1α (HIF-1a) by immunohistochemical staining, and autophagic vacuoles by transmission electron microscopy. Moreover, the mTOR signaling pathway and LC3II, p62, and HIF-1a expression were measured by western blotting. Results:Rapamycin alleviated the pathological damage of myocardial tissue, attenuated cardiac dysfunction (left ventricular ejection fraction (LVEF), p < 0.05; fractional shortening (FS), p < 0.05), and reduced HIF-1a expression (p < 0.05). Expectedly, rapamycin decreased the activity of the mTOR pathway in both sham-operated rats (p < 0.0001) and CLP rats (p < 0.01). Interestingly, we also found inhibition of the mTOR pathway in CLP rats compared with sham-operated rats; phosphorylation of both mTOR (p < 0.001) and pS6K1 (p < 0.01) was significantly suppressed following CLP challenge. Furthermore, autophagic processes were elevated by CLP; the ratio of LC3II/LC3I (p < 0.05) was increased while p62 expression (p < 0.001) was decreased significantly; there were also more autophagic vacuoles in CLP rats; and rapamycin could further elevate the autophagic processes compared with CLP rats (LC3II/LC3I, p < 0.05; P62, p < 0.05). Conclusion:Inhibition of the mTOR pathway has cardioprotective effects on myocardial dysfunction during sepsis induced by CLP, which is partly mediated through autophagy.

journal_name

Mediators Inflamm

journal_title

Mediators of inflammation

authors

Han W,Wang H,Su L,Long Y,Cui N,Liu D

doi

10.1155/2018/4798209

subject

Has Abstract

pub_date

2018-06-28 00:00:00

pages

4798209

eissn

0962-9351

issn

1466-1861

journal_volume

2018

pub_type

杂志文章

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Inhibition of the mTOR Pathway Exerts Cardioprotective Effects Partly through Autophagy in CLP Rats.