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Cardiovascular Research Advance Access first published online on March 19, 2009
This version [Corrected Proof] published online on April 9, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp094
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

The targeting of cyclophilin D by RNAi as a novel cardioprotective therapy: evidence from two-photon imaging

Masashi Kato1, Masaharu Akao1,*, Madoka Matsumoto-Ida1, Takeru Makiyama1, Moritake Iguchi1, Toshihiro Takeda1, Shigeomi Shimizu2 and Toru Kita1

1 Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
2 Department of Pathological Cell Biology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku 113-8510, Tokyo, Japan

* Corresponding author. Tel: +81 75 751 3187; fax: +81 75 752 1084. E-mail address: akao{at}kuhp.kyoto-u.ac.jp

Aims: An opening of the mitochondrial permeability transition pore (MPTP), which leads to the loss of mitochondrial membrane potential ({Delta}{Psi}m), is the earliest event that commits cells to death, and this process is potentially a prime target for therapeutic intervention against myocardial ischaemia/reperfusion. We aimed to investigate the protective effects of RNA interference (RNAi)-mediated gene silencing of cyclophilin D (CypD), one of the putative components of the MPTP, against myocardial ischaemia/reperfusion using two-photon laser scanning microscopy.

Methods and results: We created an adenovirus carrying short-interfering RNA (siRNA) that inactivates CypD. Transduction of CypD-siRNA in rat cardiomyocytes achieved a 61% reduction in CypD mRNA and a 63% reduction in protein levels as well as protection against oxidant-induced {Delta}{Psi}m loss and cytotoxicity. To further investigate the effects in vivo, we monitored the spatio-temporal changes of {Delta}{Psi}m in perfused rat hearts subjected to ischaemia/reperfusion using two-photon imaging. Adult rats received direct intramyocardial injections of the adenovirus. Two to three days after injection, rat hearts were perfused by the Langendorff method and {Delta}{Psi}m levels of individual cells were monitored. The progressive loss of {Delta}{Psi}m during ischaemia/reperfusion was significantly suppressed in CypD-siRNA-transduced cells compared with non-transduced cells. Furthermore, the protective effect of CypD-siRNA was dose-dependent.

Conclusion: Therapeutic interventions designed to inactivate CypD may be a promising strategy for reducing cardiac injury against myocardial ischaemia/reperfusion. The two-photon imaging technique provides deeper insight into cardioprotective therapy that targets mitochondria.

KEYWORDS Cyclophilin D; Ischaemia/reperfusion; Mitochondrial permeability transition; Two-photon imaging; Cardioprotection

Time for primary review: 28 days


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