Puerarin Induces Angiogenesis in Myocardium of Rat with Myocardial Infarction

Sanyin Zhang, Shilin Chen, Yingjun Shen, Dajian Yang, Xijing Liu, Albert Chan Sun-chi, Hongxi Xu
2006 Biological and Pharmaceutical Bulletin  
Puerarin [4H-1-benzopyran-4-one,8-b-D-glucopyranosyl-7-hydroxy-3-(4-hydroxyphenyl), C 21 H 20 C 9 ] is a major active ingredient extracted from the traditional Chinese medicine Ge-gen (Radix Puerariae, RP). The uses of Ge-gen described in pharmacopoeias and in traditional systems of medicine are for the treatment of fever, pain, diabetes, measles, acute dysentery or diarrhea, etc. 1) Puerarin has been shown to be able to block the beta adreno-receptor of isolated organs and the whole animal. 2)
more » ... In addition, it possesses anti-convulsive activity. 3) It suppresses alcohol intake, 4) attenuates the hyperthermia produced by 2,4-dinitrophenol 5) and improves retinal functions. 6) In particular, it has long been used to treat cardiovascular diseases including coronary artery diseases (CAD), 7) arrhythmia 8) and hypertension. 9) Moreover, some studies of the mechanisms of puerarin on CAD have shown that, for example, puerarin could recovery left ventricular function and increase coronary blood flow. 10) It also decreased myocardial lactate production, myocardial oxygen consumption, creatine phosphokinase (CPK) release and the degree of ischemic damage. 11) In addition, it improved the opening and forming of coronary collateral circulation, inhibits the increase of platelet aggregation and blood viscosity during acute myocardial infarction (AMI). 12,13) It lowered the plasma levels of free fatty acids, matrix metalloproteinases-9, C-reactive protein, serum interleukin-6 (IL-6) and tumor necrosis factor-a (TNF-a), inhibited inflammation and stabilized atherosclerotic plaque. 14,15) It played an important role in regulating the imbalance of endothelin (ET), renin activity (RA), angiotensin I (AT-I) and nitric oxide (NO) of patients with AMI, 16, 17) etc. However, the exact mechanisms of puerarin on CAD are still not very clear. Angiogenic therapy for the human heart is currently being vigorously pursued. In the past ten years, alternative revascularization/angiogenesis strategies have progressed from bench to bedside. However, most of the strategies involve the delivery of growth factors in which very little success with these strategies has been demonstrated so far for various reasons. Puerarin has been reported to improve the opening and forming of coronary collateral circulation, inhibit the increase of platelet aggregation and the blood viscosity during AMI. 12,13) Moreover, puerarin showed protective effects in endothelial dysfunction induced by lipid peroxide, chemical hypoxia, and hydroxyl-free radicals. [18] [19] [20] Puerarin could also increase the number of endothelial progenitor cell (EPC) as well as EPC proliferative, migratory, adhesive, and in vitro vasculogenesis capacity in a concentration and time-dependent manner. 21) EPCs have the ability to circulate, proliferate, and differentiate into mature endothelial cells. In additional, puerarin has been shown to promote endothelial cell proliferation. 22) Endothelial cells elongate and align to form a sprout, and the lumen is formed by a curvature inside each endothelial cell. Individual sprouts elongate and eventually join with each other forming loops through which blood begins to flow. 23) Endothelial cells retain the capacity to divide and form new blood vessels in response to specific stimuli in adult tissues. 24) Since the effect of puerarin on angiogenesis in ischemic myocardium has not been investigated previously, we hypothesized that puerarin could induce angiogenesis in ischemic and non-ischemic myocardium, leading to the curing of ischemic heart disease. MATERIALS AND METHODS Rat Myocardial Infarction Model All the experiment were performed on Sprague-Dawley male rats weighing 250-350 g and kept under standardized housing condition. The temperature in the chamber was maintained at 22-24°C. All the animals were maintained on a 12 h light/dark cycle. Puerarin is a major effective ingredient extracted from the traditional Chinese medicine Ge-gen (Radix Puerariae, RP). Recently, puerarin has been used to treat patients with coronary artery diseases (CAD). However, the mechanisms of puerarin on coronary artery diseases are still not very clear. In this study, we investigated the role of puerarin on angiogenesis in the non-ischemic and ischemic myocardium. We found that puerarin (120, 60 mg/kg, i.p.) could reduce infarct area in the heart of rat with myocardial infarction (MI). Puerarin (120 mg/kg) induced angiogenesis in the non-ischemic and ischemic myocardium, which was one of the mechanisms of curing coronary artery diseases. The gene expression or activation of vascular endothelial growth factor (VEGF), hypoxia-inducible factor 1a a (HIF-1a a) and endothelial nitric oxide synthase (eNOS) that correlated with angiogenesis were also induced by puerarin. From these results, we suggested that puerarin may induce therapeutic angiogenesis in myocardium of rat with MI. The mechanism may be that puerarin can induce VEGF and eNOS expression. Key words angiogenesis; puerarin; myocardial infarction; vascular endothelial growth factor (VEGF); endothelial nitric oxide synthase (eNOS); hypoxia-inducible factor 1a (HIF-1a)
doi:10.1248/bpb.29.945 pmid:16651724 fatcat:2abmecb23vcyxjbsf7kat7doae