Journal
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
Volume 44, Issue 1, Pages 105-113Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2007.10.006
Keywords
phosphodiesterase inhibitor; potassium channel; ischemia-reperfusion; cardioprotection; small interfering RNA
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Funding
- NHLBI NIH HHS [HL-59469, HL-51045, HL-79424] Funding Source: Medline
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL051045, R37HL051045, R01HL079424, R01HL059469] Funding Source: NIH RePORTER
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Sildenafil (Viagra), a phosphodiesterase type-5 inhibitor used in treatment of male erectile dysfunction and pulmonary hypertension can induce cardioprotection through opening of mitochondrial ATP-sensitive K channels (mitoK(ATP)). Recent studies suggest that activation of mitochondrial Ca2+-activated K+ channels (mitoK(Ca)) also has anti-ischemic effects. However, the relative role of mitoK(Ca) and mitoK(ATP) in sildenafil-induced cardioprotection remains unknown. In the present study, adult male ICR mice were pretreated with sildenafil (0.71 mg/kg, i.p.) 24 h prior to 20 min of global ischemia followed by 30 min of reperfusion in Langendorff mode. Paxilline (blocker of K-Ca) or 5-hydroxydecanoic acid (5-HD; blocker of mitoK(ATP)) was administered either 30 min before sildenafil or 10 min prior to ischemia. Treatment with sildenafil reduced infarct size, which was abolished by either paxilline or 5-HD. Furthermore, in vivo gene knockdown of beta 1 subunit of K-Ca (K-Ca-beta 1) using small interfering RNA (siRNA) administered 48 h before sildenafil injection blocked the infarct limiting effect of sildenafil. The protective effect of sildenafil was preserved in mice treated with non-target siRNA. Western blots demonstrated selective protein expression of K-Ca-beta 1 in cardiac mitochondria and the gene knockdown effect of siRNA on K-Ca-beta 1. The level of K-Ca-beta 1 protein was not upregulated following treatment with sildenafil. We conclude that both mitoK(Ca) and mitoK(ATP) play a critical role in triggering and mediating sildenafil-induced delayed cardioprotection. The results suggest that activation of mitoK(Ca) and mitoK(ATP) are crucial for maintaining mitochondrial homeostasis and reducing cell death in sildenafil-induced preconditioning against ischemia-reperfusion injury. (C) 2007 Elsevier Inc. All rights reserved.
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