0546 : Mitochondrial induced oxidative stress triggers Ca2+-dependent proteolysis and underlie VIDD

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• 作者：Haikel Dridi ; ^{dridi.haikel1@gmail.com" class="auth_mail" title="E-mail the corresponding author}
• 刊名：Archives of Cardiovascular Diseases Supplements
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：8
• 期：3
• 页码：217
• 全文大小：50 K

文摘

In rodents, prolonged controlled mechanical ventilation (CMV) and associated diaphragm inactivity elicits complex pathologic changes referred to as ventilator-induced diaphragm dysfunction (VIDD). Previous workers have demonstrated that VIDD is characterized by increased mitochondrial generation of reactive oxygen species (ROS) and redox-induced dysfunction in calcium release. Powers et al., (2011) have demonstrated that SS-31, a mitochondrial targeted antioxidant, markedly attenuates mitochondrial ROS generation. Since, the calcium-release pathology associated with VIDD is thought to be secondary to myofiber redox changes, we hypothesized that SS-31 should markedly attenuate these abnormalities in myofiber calcium regulation.

Objective

To test the hypothesis that SS-31, a mitochondrial-targeted antioxidant, attenuates the effect of prolonged CMV on diaphragm myofiber calcium homeostasis.

Measurements and main results

Specific force of diaphragm fibers decreased significantly 28 ±5%, (n=10) following 12hrs of mechanical ventilation compared to fibers from unventilated control mice. These changes were associated with a significant decrease in cross-sectional area (574 ±19 versus 673± 21 μm2), an increase in calpain activity, the oxidation of the RyR1 macromolecular complexed, RyR1 phosphorylation at Ser-2844 and the depletion of the stabilizing subunit calstabin1 resulting in an increase in sarcoplasmic reticulum (SR) Ca2+ leak. Diaphragm from mice treated with SS-31 were protected against all of these changes.

On the basis of these findings

we propose that SR Ca2+ leak via RyR1 due to mitochondrial induced oxidative stress, triggers Ca2+-dependent proteolysis and underlie VIDD. These results emphasize the need to develop therapeutic interventions that mitigate mitochondrial dysfunctional thereby reduce mechanical ventilation-induced diaphragmatic weakness.

The author hereby declares no conflict of interest