Disruption of caveolae blocks ischemic preconditioning-mediated S-nitrosylation of mitochondrial proteins

Junhui Sun, Mark J. Kohr, Tiffany Nguyen, Angel M. Aponte, Patricia S. Connelly, Shervin G. Esfahani, Marjan Gucek, Mathew P. Daniels, Charles Steenbergen, Elizabeth Murphy

Research output: Contribution to journalArticle

Abstract

Aims: Nitric oxide (NO) and protein S-nitrosylation (SNO) play important roles in ischemic preconditioning (IPC)-induced cardioprotection. Mitochondria are key regulators of preconditioning, and most proteins showing an increase in SNO with IPC are mitochondrial. The aim of this study was to address how IPC transduces NO/SNO signaling to mitochondria in the heart. Results: In this study using Langendorff perfused mouse hearts, we found that IPC-induced cardioprotection was blocked by treatment with either N-nitro-L-arginine methyl ester (L-NAME, a constitutive NO synthase inhibitor), ascorbic acid (a reducing agent to decompose SNO), or methyl-β-cyclodextrin (MβCD, a cholesterol sequestering agent to disrupt caveolae). IPC not only activated AKT/eNOS signaling but also led to translocation of eNOS to mitochondria. MβCD treatment disrupted caveolar structure, leading to dissociation of eNOS from caveolin-3 and blockade of IPC-induced activation of the AKT/eNOS signaling pathway. A significant increase in mitochondrial SNO was found in IPC hearts compared to perfusion control, and the disruption of caveolae by MβCD treatment not only abolished IPC-induced cardioprotection, but also blocked the IPC-induced increase in SNO. Innovation: These results provide mechanistic insight into how caveolae/eNOS/NO/SNO signaling mediates cardioprotection induced by IPC. Conclusion: Altogether these results suggest that caveolae transduce eNOS/NO/SNO cardioprotective signaling in the heart.

Original languageEnglish (US)
Pages (from-to)45-56
Number of pages12
JournalAntioxidants and Redox Signaling
Volume16
Issue number1
DOIs
StatePublished - Jan 1 2012

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

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    Sun, J., Kohr, M. J., Nguyen, T., Aponte, A. M., Connelly, P. S., Esfahani, S. G., Gucek, M., Daniels, M. P., Steenbergen, C., & Murphy, E. (2012). Disruption of caveolae blocks ischemic preconditioning-mediated S-nitrosylation of mitochondrial proteins. Antioxidants and Redox Signaling, 16(1), 45-56. https://doi.org/10.1089/ars.2010.3844