caa a22 4500 606158456 CHVBK 20210128100619.0 cr unu---uuuuu 210128e20150601xx s 000 0 eng 10.1007/s10557-015-6592-7 doi (NATIONALLICENCE)springer-10.1007/s10557-015-6592-7 Preservation of Glucagon-Like Peptide-1 Level Attenuates Angiotensin II-Induced Tissue Fibrosis by Altering AT1/AT2 Receptor Expression and Angiotensin-Converting Enzyme 2 Activity in Rat Heart [Elektronische Daten] [Li-Hui Zhang, Xue-Fen Pang, Feng Bai, Ning-Ping Wang, Ahmed Shah, Robert McKallip, Xue-Wen Li, Xiong Wang, Zhi-Qing Zhao] Purpose: The glucagon-like peptide-1 (GLP-1) has been shown to exert cardioprotective effects in animals and patients. This study tests the hypothesis that preservation of GLP-1 by the GLP-1 receptor agonist liraglutide or the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin is associated with a reduction of angiotensin (Ang) II-induced cardiac fibrosis. Methods and Results: Sprague-Dawley rats were subjected to Ang II (500ng/kg/min) infusion using osmotic minipumps for 4weeks. Liraglutide (0.3mg/kg) was subcutaneously injected twice daily or linagliptin (8mg/kg) was administered via oral gavage daily during Ang II infusion. Relative to the control, liraglutide, but not linagliptin decreased MAP (124 ± 4 vs. 200 ± 7mmHg in control, p < 0.003). Liraglutide and linagliptin comparatively reduced the protein level of the Ang II AT1 receptor and up-regulated the AT2 receptor as identified by a reduced AT1/AT2 ratio (0.4 ± 0.02 and 0.7 ± 0.01 vs. 1.4 ± 0.2 in control, p < 0.05), coincident with the less locally-expressed AT1 receptor and enhanced AT2 receptor in the myocardium and peri-coronary vessels. Both drugs significantly reduced the populations of macrophages (16 ± 6 and 19 ± 7 vs. 61 ± 29 number/HPF in control, p < 0.05) and α-SMA expressing myofibroblasts (17 ± 7 and 13 ± 4 vs. 66 ± 29 number/HPF in control, p < 0.05), consistent with the reduction in expression of TGFβ1 and phospho-Smad2/3, and up-regulation of Smad7. Furthermore, ACE2 activity (334 ± 43 and 417 ± 51 vs. 288 ± 19 RFU/min/μg protein in control, p < 0.05) and GLP-1 receptor expression were significantly up-regulated. Along with these modulations, the synthesis of collagen I and tissue fibrosis were inhibited as determined by the smaller collagen-rich area and more viable myocardium. Conclusion: These results demonstrate for the first time that preservation of GLP-1 using liraglutide or linagliptin is effective in inhibiting Ang II-induced cardiac fibrosis, suggesting that these drugs could be selected as an adjunctive therapy to improve clinical outcomes in the fibrosis-derived heart failure patients with or without diabetes. Springer Science+Business Media New York, 2015 Angiotensin II receptors nationallicence ACE2 nationallicence Collagen nationallicence Cardiac fibrosis nationallicence Dipeptidyl peptidase-4 nationallicence Glucagon-like peptide-1 nationallicence Zhang Li-Hui Department of Cardiology, Shanxi Medical University, Shanxi Dayi Hospital, Taiyuan, Shanxi, China aut Pang Xue-Fen Department of Physiology, Shanxi Medical University, Taiyuan, Shanxi, China aut Bai Feng Department of Cardiology, Shanxi Medical University, Shanxi Dayi Hospital, Taiyuan, Shanxi, China aut Wang Ning-Ping Cardiovascular Research Laboratory, Mercer University School of Medicine, Savannah, GA, USA aut Shah Ahmed Department of Internal Medicine, Mercer University School of Medicine, Macon, GA, USA aut McKallip Robert Division of Basic Biomedical Sciences, Mercer University School of Medicine, Macon, GA, USA aut Li Xue-Wen Department of Cardiology, Shanxi Medical University, Shanxi Dayi Hospital, Taiyuan, Shanxi, China aut Wang Xiong Department of Cardiology, Shanxi Medical University, Shanxi Dayi Hospital, Taiyuan, Shanxi, China aut Zhao Zhi-Qing Department of Physiology, Shanxi Medical University, Taiyuan, Shanxi, China aut Cardiovascular Drugs and Therapy Springer US; http://www.springer-ny.com 29/3(2015-06-01), 243-255 0920-3206 29:3<243 2015 29 10557 https://doi.org/10.1007/s10557-015-6592-7 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s10557-015-6592-7 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Zhang Li-Hui Department of Cardiology, Shanxi Medical University, Shanxi Dayi Hospital, Taiyuan, Shanxi, China aut NATIONALLICENCE 700 1- Pang Xue-Fen Department of Physiology, Shanxi Medical University, Taiyuan, Shanxi, China aut NATIONALLICENCE 700 1- Bai Feng Department of Cardiology, Shanxi Medical University, Shanxi Dayi Hospital, Taiyuan, Shanxi, China aut NATIONALLICENCE 700 1- Wang Ning-Ping Cardiovascular Research Laboratory, Mercer University School of Medicine, Savannah, GA, USA aut NATIONALLICENCE 700 1- Shah Ahmed Department of Internal Medicine, Mercer University School of Medicine, Macon, GA, USA aut NATIONALLICENCE 700 1- McKallip Robert Division of Basic Biomedical Sciences, Mercer University School of Medicine, Macon, GA, USA aut NATIONALLICENCE 700 1- Li Xue-Wen Department of Cardiology, Shanxi Medical University, Shanxi Dayi Hospital, Taiyuan, Shanxi, China aut NATIONALLICENCE 700 1- Wang Xiong Department of Cardiology, Shanxi Medical University, Shanxi Dayi Hospital, Taiyuan, Shanxi, China aut NATIONALLICENCE 700 1- Zhao Zhi-Qing Department of Physiology, Shanxi Medical University, Taiyuan, Shanxi, China aut NATIONALLICENCE 773 0- Cardiovascular Drugs and Therapy Springer US; http://www.springer-ny.com 29/3(2015-06-01), 243-255 0920-3206 29:3<243 2015 29 10557