Liraglutide attenuates cardiac remodeling and improves heart function after abdominal aortic constriction through blocking angiotensin II type 1 receptor in rats

• Published in: Drug design, development and therapy Vol. 13; pp. 2745 - 2757
• Main Authors: Zheng, Rong-Hua, Bai, Xiao-Jie, Zhang, Wei-Wei, Wang, Jing, Bai, Feng, Yan, Cai-Ping, James, Erskine A, Bose, Himangshu S, Wang, Ning-Ping, Zhao, Zhi-Qing
• Format: Journal Article
• Language: English
• Published: New Zealand Dove Medical Press Limited 01.08.2019; Taylor & Francis Ltd; Dove; Dove Medical Press
• Subjects: Abdomen; ACE2; Angiotensin; Angiotensin converting enzyme; Angiotensin II; angiotensin II AT1 receptor; Angiotensin-converting enzyme 2; Angiotensins; Animals; Aorta; Bioengineering; Blood pressure; Brain natriuretic peptide; cardiac fibrosis; cardiac function; Cardiomyocytes; Cardiovascular system; Collagen; Collagen (type I); Congestive heart failure; Constriction, Pathologic - drug therapy; Constriction, Pathologic - metabolism; Coronary vessels; Dose-Response Relationship, Drug; Drug dosages; Echocardiography; Enzymes; Fibrosis; Glucagon; Glucagon-like peptide 1; Glucose; Growth factors; Heart; Heart - drug effects; Heart attacks; Heart failure; Heart function; Hypertension; Hypertrophy; Injections, Subcutaneous; Laboratory animals; Levels; Lipid peroxidation; Liraglutide; Liraglutide - administration & dosage; Liraglutide - pharmacology; Macrophages; Male; Malondialdehyde; Medical research; Myocardium; Natriuretic peptides; Original Research; Oxidative stress; Pathogenesis; Peptides; Physiology; Proteins; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1 - agonists; Receptor, Angiotensin, Type 1 - metabolism; Rodents; Signal transduction; Smad2 protein; Smad7 protein; Superoxide dismutase; Superoxides; Systolic pressure; Telmisartan; Transforming growth factor-b1; Type 2 diabetes; Ventricle; Ventricular Remodeling - drug effects; China; United States > US; liraglutide; angiotensin II AT1 receptor; cardiac function; cardiac fibrosis; telmisartan
• ISSN: 1177-8881; 1177-8881
• DOI: 10.2147/DDDT.S213910

Angiotensin II (Ang II) is known to contribute to the pathogenesis of heart failure by eliciting cardiac remodeling and dysfunction. The glucagon-like peptide-1 (GLP-1) has been shown to exert cardioprotective effects in animals and patients. This study investigates whether GLP-1 receptor agonist liraglutide inhibits abdominal aortic constriction (AAC)-induced cardiac fibrosis and dysfunction through blocking Ang II type 1 receptor (AT1R) signaling. Sprague-Dawley rats were subjected to sham operation and abdominal aortic banding procedure for 16 weeks. In treated rats, liraglutide (0.3 mg/kg) was subcutaneously injected twice daily or telmisartan (10 mg/kg/day), the AT1R blocker, was administered by gastric gavage. Relative to the animals with AAC, liraglutide reduced protein level of the AT1R and upregulated the AT2R, as evidenced by reduced ratio of AT1R/AT2R (0.59±0.04 vs. 0.91±0.06, <0.05). Furthermore, the expression of angiotensin converting enzyme 2 was upregulated, tissue levels of malondialdehyde and B-type natriuretic peptide were reduced, and superoxide dismutase activity was increased. Along with a reduction in HW/BW ratio, cardiomyocyte hypertrophy was inhibited. In coincidence with these changes, liraglutide significantly decreased the populations of macrophages and myofibroblasts in the myocardium, which were accompanied by reduced protein levels of transforming growth factor beta1, Smad2/3/4, and upregulated smad7. The synthesis of collagen I and III was inhibited and collagen-rich fibrosis was attenuated. Consistent with these findings, cardiac systolic function was preserved, as shown by increased left ventricular systolic pressure (110±5 vs. 99±2 mmHg, <0.05), ejection fraction (83%±2% vs. 69%±4%, <0.05) and fraction shortening (49%±2% vs. 35%±3%, <0.05). Treatment with telmisartan provided a comparable level of protection as compared with liraglutide in all the parameters measured. Taken together, liraglutide ameliorates cardiac fibrosis and dysfunction, potentially via suppressing the AT1R-mediated events. These data indicate that liraglutide might be selected as an add-on drug to prevent the progression of heart failure.