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

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

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Caveolae
Ischemic Preconditioning
Mitochondrial Proteins
Mitochondria
Nitric Oxide
Sequestering Agents
Caveolin 3
Arginine
Protein S
NG-Nitroarginine Methyl Ester
Reducing Agents
Cyclodextrins
Nitric Oxide Synthase
Ascorbic Acid
Esters
Innovation
Chemical activation
Cholesterol
Heart Mitochondria
Proteins

ASJC Scopus subject areas

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

Cite this

Disruption of caveolae blocks ischemic preconditioning-mediated S-nitrosylation of mitochondrial proteins. / Sun, Junhui; Kohr, Mark; Nguyen, Tiffany; Aponte, Angel M.; Connelly, Patricia S.; Esfahani, Shervin G.; Gucek, Marjan; Daniels, Mathew P.; Steenbergen, Charles Jr; Murphy, Elizabeth.

In: Antioxidants and Redox Signaling, Vol. 16, No. 1, 01.01.2012, p. 45-56.

Research output: Contribution to journalArticle

Sun, Junhui ; Kohr, Mark ; Nguyen, Tiffany ; Aponte, Angel M. ; Connelly, Patricia S. ; Esfahani, Shervin G. ; Gucek, Marjan ; Daniels, Mathew P. ; Steenbergen, Charles Jr ; Murphy, Elizabeth. / Disruption of caveolae blocks ischemic preconditioning-mediated S-nitrosylation of mitochondrial proteins. In: Antioxidants and Redox Signaling. 2012 ; Vol. 16, No. 1. pp. 45-56.
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