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

Abstract

Objective 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. Methods 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. Results 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, p <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, p <0.05), ejection fraction (83%±2% vs. 69%±4%, p <0.05) and fraction shortening (49%±2% vs. 35%±3%, p <0.05). Treatment with telmisartan provided a comparable level of protection as compared with liraglutide in all the parameters measured. Conclusion 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.

Liraglutide Attenuates Myocardial Fibrosis via Inhibition of AT1R-Mediated ROS Production in Hypertensive Mice

“…A recent study by Zheng et al demonstrated that liraglutide attenuated cardiac fibrosis and improved heart function via blocking AT1R in rats. 35 In this study, we further proved that the anti-diabetic drug liraglutide can prevent AT1R-ROS signaling. Indeed, AT1R-mediated ROS production in cardiovascular system and its relevance have been recently discussed.…”

“…Actually, a recent study reported liraglutide and telmisartan (another AT1 blocker) both markedly improved cardiac performance of hypertensive rats. 35…”

“…Actually, a recent study reported liraglutide and telmisartan (another AT1 blocker) both markedly improved cardiac performance of hypertensive rats. 35 Cardiac fibroblasts account for approximately 25% of myocardial volume and 60% of all cells in the heart in the physiologic state. 39 In the pathological state, cardiac fibroblasts proliferate, become activated in response to neurohormonal changes such as heightened levels of Ang II, and produce collagen.…”

Matrix metalloproteinase 3 regulates angiotensin II‑induced myocardial fibrosis cell viability, migration and apoptosis

“…Furthermore, Axl, which is activated by growth arrest-specific 6, was upregulated in patients with HF and MF, and was used to predict the adverse pathology of cardiovascular disease ( 16 , 40 ). AT1R can interact with AngII and promote tissue fibrotic formation ( 17 ). Previous studies have also demonstrated that pharmacological inhibition of AT1R may significantly reduce cardiac fibrosis and improve cardiac function ( 41 , 42 ).…”

“…AXL receptor tyrosine kinase (Axl) has been utilized to predict the adverse pathology of MF ( 16 ). Moreover, angiotensin II receptor type 1 (AT1R) has been reported to interact with angiotensin II (AngII) and promote the formation of tissue fibrosis ( 17 ). In addition, Zachariah et al ( 18 ) reported that circulating matrix metalloproteinase (MMP)3 may serve as a marker of MF and ventricular arrhythmia in adolescents with hypertrophic cardiomyopathy.…”