Abstract 576: Nrf2 is a Key Regulator on Puerarin Preventing Cardiac Hypertrophy and Upregulating Metabolic Enzymes Ugt1a1 and Ugt1a9 in Rats

• Published in: Circulation research 2018-08, Vol.123 (Suppl_1)
• Main Authors: Hou, Ning, Zhao, Ganjian, Cai, Shaoai, Liu, Xiawen, Li, Aiqun, Huang, Yin, Li, Lirong, Luo, Chengfeng
• Format: Article
• Language: English
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/res.123.suppl_1.576

Abstract only Previous evidence suggested that puerarin may attenuate cardiac hypertrophy; however, the potential mechanisms were undetermined. Moreover, the use of puerarin is limited by severe adverse events, including intravascular hemolysis. This study used a rat model of abdominal aortic constriction (AAC) -induced cardiac hypertrophy to evaluate the potential mechanisms underlying the attenuating efficacy of puerarin on cardiac hypertrophy as well as the metabolic mechanisms of puerarin involved. We confirmed that puerarin (50 mg/kg/d) significantly attenuated cardiac hypertrophy, upregulated Nrf2 and decreased Keap1 in the myocardium. Moreover, puerarin significantly promoted Nrf2 translocation to the nucleus in parallel with the upregulated downstream proteins including heme oxygenase-1, glutathione s-transferase p-1 and NAD(P)H: quinone oxidoreductase-1. Similar results were obtained in neonatal rat cardiomyocytes (NRCMs) treated with angiotensin II (1 μM) and puerarin (100 μM), while the silencing of Nrf2 abolished the antihypertrophic effects of puerarin. The mRNA and protein levels of UGT1A1 and UGT1A9, enzymes for puerarin metabolism, were significantly increased in the liver and heart tissues of AAC rats and angiotensin II-treated NRCMs. Interestingly, the silencing of Nrf2 attenuated the puerarin-induced upregulation of UGT1A1 and UGT1A9. The results of chromatin immunoprecipitation-qPCR indicated that the binding of Nrf2 to the promoter region of UGT1A1 or UGT1A9 was significantly enhanced in puerarin-treated cardiomyocytes. These results suggest that Nrf2 is the key regulator of antihypertrophic effects and the upregulation of the metabolic enzymes UGT1A1 and UGT1A9 of puerarin. This autoregulatory circuits between puerarin and Nrf2-induced UGT1A1/1A9 are beneficial to attenuate adverse effects and maintain the pharmacological effects of puerarin.