Complete Induction of Autophagy Is Essential for Cardioprotection in Sepsis

Hsieh, Chi-Hsun MD^*; Pai, Pei-Ying MD^†; Hsueh, Hsiang-Wei MSc^‡; Yuan, Shyng-Shiou MD, PhD^‡; Hsieh, Ya-Ching PhD^‡

^*Department of Trauma and Emergency Surgery;

^†Department of Internal Medicine, Division of Cardiology, China Medical University Hospital, China Medical University, Taichung 404, Taiwan, ROC; and

^‡Department of Medical Research, E-Da Hospital, I-Shou University, Kaohsiung 824, Taiwan, ROC

Reprints: Ya-Ching Hsieh, PhD, Department of Medical Research, E-Da Hospital/I-Shou University, 6 Yi-Da Road, Kaohsiung county 824, Taiwan, ROC. E-mail:[email protected].

Supported by E-Da Hospital grant EDAHT98011 (Ya-Ching Hsieh), National Science Council grant NSC-98–2320-B-650–001-MY2 (Ya-Ching Hsieh), and NSC 97-2314-B-039 -008 -MY3 (Chi-Hsun Hsieh).

Annals of Surgery253(6):p 1190-1200, June 2011. |DOI:10.1097/SLA.0b013e318214b67e

Objective:

To investigate the entire process of autophagy in the left ventricle of septic mice, and the functional significance of autophagy by using pharmacological agents.

Background:

Myocardial dysfunction is a common feature in sepsis and contributes to an increased risk of developing multiple organ failure. Autophagy functions predominantly as a prosurvival pathway in the heart during cellular stress. A dynamic process of autophagy that involves the complete activation of autophagy from autophagosome formation to fusion with lysosomes has driven the development of new approaches to detecting autophagy.

Methods:

Male mice were subjected to cecal ligation and puncture (CLP) or sham operation. At 1 hour after CLP operation, mice received either rapamycin (induction of autophagy), bafilomycin A1 (inhibition of autophagosomal degradation), or vehicle.

Results:

The formation of autophagosomes was increased whereas the degradation of autophagosomes was decreased in the left ventricle at 24 hours after CLP. This was consistent with the morphologic finding that septic hearts revealed an increase in autophagosomes but few autolysosomes, indicating incompletion of the autophagic process. Rapamycin, which induced complete activation of autophagy, restored CLP-induced depressed cardiac performances. This cardioprotective effect was also seen in increased ATP levels, and decreased inflammatory responses. Bafiomycin A1, which resulted in incompletion of the autophagic process, did not show any above beneficial effects in CLP mice.

Conclusions:

Incompletion of the autophagic process may contribute to sepsis-induced cardiac dysfunction. Treatment with rapamycin may serve a cardioprotective role in sepsis, possibly through the effect of complete induction of autophagy.