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ORIGINAL RESEARCH ARTICLE

Anti-Apoptotic Effect of Magnolol in Myocardial Ischemia and Reperfusion Injury Requires Extracellular Signal-Regulated Kinase1/2 Pathways in Rat In Vivo

Yong Chun Jin^*, Kil Jung Kim^*, Young Min Kim^*, Yu Mi Ha^*, Hye Jung Kim^*, Ui Jung Yun, Ki Hwan Bae, Yeong Shik Kim, Sam Sik Kang, Han Geuk Seo^*, Jae Heun Lee^* and Ki Churl Chang^*,1

^* Department of Pharmacology, School of Medicine and Institute of Health Sciences, Gyeongsang National University, Jinju, Korea; College of Pharmacy, Chungnam National University, Daejeon, Korea; and Natural Product Research Institute, College of Pharmacy, Seoul National University, Seoul, Korea

To whom requests for reprints should be addressed at ¹ Department of Pharmacology, School of Medicine and Institute of Health Sciences, Gyeongsang National University, 92 Chilamdong, Jinju, 660–751, Korea. E-mail: kcchang{at}gnu.kr

Magnolol, an active component extracted from Magnolia officinalis, has been reported to have protective effect on ischemia and reperfusion (I/R)-induced injury in experimental animals. The aim of the present investigation was to further evaluate the mechanism(s) by which magnolol reduces I/R-induced myocardial injury in rats in vivo. Under anesthesia, left anterior descending (LAD) coronary artery was occluded for 30 min followed by reperfusion for 24 h (for infarct size and cardiac function analysis). In some experiments, reperfusion was limited to 1 h or 6 h for analysis of biochemical and molecular events. Magnolol and DMSO solution (vehicle) were injected intra-peritoneally 1 h prior to I/R insult. The infarct size was measured by TTC technique and heart function was monitored by Millar Catheter. Apoptosis related events such as p-ERK, p-Bad, Bcl-xl and cytochrome c expression were evaluated by Western blot analysis and myocardial caspase-3 activity was also measured. Magnolol (10 mg/kg) reduced infarct size by 50% (P < 0.01 versus vehicle), and also improved I/R-induced myocardial dysfunction. Left ventricular systolic pressure and positive and negative maximal values of the first derivative of left ventricular pressure (dP/dt) were significantly improved in magnolol-treated rats. Magnolol increased the expression of phosphor ERK and Bad which resulted in inhibition of myocardial apoptosis as evidenced by TUNEL analysis and DNA laddering experiments. Application of PD 98059, a selective MEK1/2 inhibitor, strongly antagonized the effect of magnolol. Taken together, we concluded that magnolol inhibits apoptosis through enhancing the activation of ERK1/2 and modulation of the Bcl-xl proteins which brings about reduction of infarct size and improvement of cardiac function in I/R-induced injury.

Key Words: magnolol • I/R injury • apoptosis • ERK1/2 • rat