Journal of Ethnopharmacology 139 (2012) 605–615 Contents lists available at SciVerse ScienceDirect Journal of Ethnopharmacology journa l h o me page: www.elsevier.com/locate/jethpharm 2-Methoxycinnamaldehyde from Cinnamomum cassia reduces rat myocardial ischemia and reperfusion injury in vivo due to HO-1 induction Jeong Seok Hwa a,1 , Yong Chun Jin e,1 , Young Soo Lee b , Young Shin Ko b , Young Min Kim b , Lian Yu Shi f , Hye Jung Kim b , Jae Heun Lee b , Tran Minh Ngoc c , Ki Hwan Bae c , Yeong Shik Kim d , Ki Churl Chang b,∗ a Department of Urology and Institute of Health Sciences, School of Medicine, Gyeongsang National University, Jinju 660-290, Republic of Korea b Department of Pharmacology and Institute of Health Sciences, School of Medicine, Gyeongsang National University, Jinju 660-290, Republic of Korea c College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea d Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul, Republic of Korea e Yanbian Second People’s Hospital, Thoracic and Vascular Surgery, Jilin, China f Department of Gynecology and Obstetrics, Yanji Anorectal Hospital, Jilin, China a r t i c l e i n f o Article history: Received 28 April 2011 Received in revised form 17 October 2011 Accepted 2 December 2011 Available online 9 December 2011 Keywords: 2-Methoxycinnamaldehyde Inflammation HMGB1 VCAM-1 Heme oxygenase-1 Ischemia Reperfusion injury a b s t r a c t Ethnopharmacological relevance: Cinnamomum cassia Blume has been used as a traditional Chinese herbal medicine for alleviation of fever, inflammation, chronic bronchitis, and to improve blood circulation. Aim of the study: We addressed whether 2-methoxycinnamaldehyde (2-MCA), one of active ingredients of Cinnamomum cassia, reduces vascular cell adhesion molecule-1 (VCAM-1) expression in tumor necrosis factor-alpha (TNF-)-activated endothelial cells and protects ischemia/reperfusion (I/R)-injury due to heme oxygenase (HO)-1 induction. Materials and methods: Adult male rats were subjected to 30 min of ischemia by occlusion of the left anterior descending coronary artery followed by 24 h of reperfusion. Rats were randomized to receive vehicle or 2-MCA (i.v.) 10 min before reperfusion. Results: Administration of 2-MCA significantly improved I/R-induced myocardial dysfunction by increas- ing the values of the first derivative (±dp/dt) of left ventricular pressure and decreased infarct size. In addition, 2-MCA reduced the expression of high mobility group box 1 (HMGB1), an activator of the inflam- matory cascade when released into the extracellular space, and VCAM-1 in I/R myocardium along with increase of HO-1 induction. The reduced injury was accompanied by significantly reduction of neutrophils infiltration and increased SOD activity in ischemic tissues and reduced serum level of cardiac troponin I (cTnI). Furthermore, 2-MCA significantly increased HO-1 induction by translocation of Nrf-2 from cytosol to nucleus in endothelial cells. Inhibition of VCAM-1 expression by 2-MCA was reversed both by SnPPIX, a HO-1 inhibitor and siHO-1 RNA trasfection in TNF--activated cells. In addition, 2-MCA significantly inhibited NF-B luciferase activity in TNF--activated endothelial cells. As expected, 2-MCA significantly inhibited monocyte (U937) adhesion to endothelial cells. Conclusion: We concluded that 2-MCA protects of myocardial I/R-injury due to antioxidant and anti- inflammatory action possibly by HO-1 induction which can be explained why Cinnamomum cassia has been used in inflammatory disorders. © 2011 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Ischemia and reperfusion (I/R) occurs in a wide range of situations including trauma, vascular reflow after contraction, percutaneous transluminal coronary angioplasty, thrombolysis treatment, and organ transplantation. In the ischemic heart, initial cardiac damage is prompted by diminished blood supply. However, ∗ Corresponding author. Tel.: +82 55 772 8071; fax: +82 55 772 8079. E-mail address: kcchang@gnu.kr (K.C. Chang). 1 These author contributed equally in this project. swift restoration of normal blood supply is imperative to min- imize cardiac injury. Unfortunately, reperfusion itself can lead to additional injury in the form of cardiac dysfunction, reperfu- sion arrhythmias, and exacerbated myocardial infarction. Oxidant stress as well as inflammation seems to play a major role for organ injury during I/R (McCord, 1985; Cross et al., 1987; Halliwell et al., 1992; Jeroudi et al., 1994; Jin et al., 2009a,b). Indeed, increased production of reactive oxygen species (ROS) and accu- mulation of calcium in the cytosol and mitochondria are major causative factors of I/R injury (Zucchi et al., 2007; Murphy and Steenbergen, 2008). Heme oxygenase (HO) is the rate-limiting enzyme that catalyzes the degradation of heme into carbon 0378-8741/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.jep.2011.12.001