Drugs in the Pipeline – Original ArticleHigenamine Improves Cardiac and Renal Fibrosis in Rats With Cardiorenal Syndrome via ASK1 Signaling PathwayDeng, Ting MD*,†,‡,§; Wei, Zhenming MD*,†,‡; Gael, Akindavyi MD*,†,‡; Deng, Xiaofang MD¶; Liu, Yunfeng MD*,†,‡; Lai, Jun MD*,†,‡; Hang, Liwei PhD*,†,‡; Yan, Quanneng PhD*,†,‡; Fu, Qiang PhD*,†,‡; Li, Zhiliang MD*,†,‡Author Information *Department of Cardiology, Laboratory of Heart Center, Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China; †Guangdong Provincial Biomedical Engineering Technology, Research Center for Cardiovascular Disease, Guangdong, China; ‡Sino-Japanese Cooperation Platform for Translational Research in the Heart Failure, Guangzhou, China; §Department of Cardiovascular Disease, First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; and ¶Guangdong Provincial People's Hospital, Guangzhou, China. Reprints: Qiang Fu, PhD or Zhiliang Li, MD, Laboratory of Heart Center, Department of Cardiology, Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China (e-mail: email@example.com or firstname.lastname@example.org). Supported by the Nature Science Foundation of China (nos. 81573732) and Guangdong Natural Science Foundation (nos. 2015A030313304). The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.jcvp.org). T. Deng and Z. Wei contributed equally to this work. Received March 24, 2019 Accepted February 20, 2020 Online date: March 11, 2020 Journal of Cardiovascular Pharmacology: June 2020 - Volume 75 - Issue 6 - p 535-544 doi: 10.1097/FJC.0000000000000822 Buy SDC Metrics Abstract The pathogenesis of cardiorenal syndrome (CRS) is very complex, and currently there is no effective treatment for CRS. Higenamine (HI) has been shown to improve cardiac function in rats with heart failure. However, the role of higenamine in CRS remains unknown. Here, in vitro, higenamine treatment markedly reduced neonatal rat cardiac fibroblast collagen synthesis and inhibited neonatal rat cardiac myocyte hypertrophy. In our study, a rat model of type 2 CRS was induced by left anterior descending coronary artery ligation combined with 5/6 subtotal nephrectomy (STNx). Higenamine treatment decreased serum creatinine (Scr), blood urea nitrogen, and brain natriuretic peptide levels and was capable of improving left ventricular remodeling and systolic function in CRS rats, accompanied with decreased expression of transforming growth factor-β1 (TGF-β1), α–smooth muscle actin (α-SMA) and collagen I (Col1A1). Moreover, higenamine significantly inhibited the protein expression of phosphorylated apoptosis signal-regulated kinase 1 (p-ASK1) and downstream mitogen-activated protein kinases (MAPK) (ERK, P38)/NF-κB in cardiorenal tissues of CRS rats and neonatal rat cardiac fibroblast/neonatal rat cardiac myocyte cells. Our study demonstrated that higenamine improved cardiorenal function in CRS rats and attenuated heart and kidney fibrosis possibly via targeting ASK1/MAPK (ERK, P38)/NF-κB signaling pathway. This finding extends our knowledge on the role of higenamine in cardiorenal fibrosis, providing a potential target to prevent the progression of CRS. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.