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Cardiovascular Research Advance Access [Accepted Manuscript] published online on March 19, 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 Kato, MD, Masaharu Akao, MD, PhD, Madoka Matsumoto-Ida, MD, PhD, Takeru Makiyama, MD, PhD, Moritake Iguchi, MD, Toshihiro Takeda, MD, PhD, Shigeomi Shimizu, MD, PhD* and Toru Kita, MD, PhD.

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

Address for correspondence: Masaharu Akao, MD, PhD, Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. Phone: +81-75-751-3187, Fax: +81-75-752-0856, E-mail: akao{at}kuhp.kyoto-u.ac.jp

Aims: An opening of the mitochondrial permeability transition pore (MPTP), which leads to 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 ischemia/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 ischemia/reperfusion by using two-photon laser scanning microscopy.

Methods and Results: We created an adenovirus carrying short interfering RNA (siRNA) which 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 ischemia/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 ischemia/reperfusion was significantly suppressed in CypD-siRNA-transduced cells compared with non-transduced cells. Furthermore, the protective effect of CypD-siRNA was dose dependent.

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

Time for primary review: 28 Days


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