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.

Angiotensin II (Ang II) is known to be involved in the progression of ventricular dysfunction and heart failure by eliciting cardiac fibrosis. The purpose of this study was to demonstrate whether treatment with an antioxidant compound, edaravone, reduces cardiac fibrosis and improves ventricular function by inhibiting Ang II AT1 receptor. The study was conducted in a rat model of transverse aortic constriction (TAC). In control, rats were subjected to 8 weeks of TAC. In treated rats, edaravone (10 mg/kg/day) or Ang II AT1 receptor blocker, telmisartan (10 mg/kg/day) was administered by intraperitoneal injection or gastric gavage, respectively, during TAC. Relative to the animals with TAC, edaravone reduced myocardial malonaldehyde level and increased superoxide dismutase activity. Protein level of the AT1 receptor was reduced and the AT2 receptor was upregulated, as evidenced by the reduced ratio of AT1 over AT2 receptor (0.57±0.2 vs 3.16±0.39, p<0.05) and less locally expressed AT1 receptor in the myocardium. Furthermore, the protein level of angiotensin converting enzyme 2 was upregulated. In coincidence with these changes, edaravone significantly decreased the populations of macrophages and myofibroblasts in the myocardium, which were accompanied by reduced levels of transforming growth factor beta 1 and Smad2/3. Collagen I synthesis was inhibited and collagen-rich fibrosis was attenuated. Relative to the TAC group, cardiac systolic function was preserved, as shown by increased left ventricular systolic pressure (204±51 vs 110±19 mmHg, p<0.05) and ejection fraction (82%±3% vs 60%±5%, p<0.05). Treatment with telmisartan provided a comparable level of protection as compared with edaravone in all the parameters measured. Taken together, edaravone treatment ameliorates cardiac fibrosis and improves left ventricular function in the pressure overload rat model, potentially via suppressing the AT1 receptor-mediated signaling pathways. These data indicate that edaravone might be selected in combination with other existing drugs in preventing progression of cardiac dysfunction in heart failure.

Increased vascular resistance in the fetoplacental circulation is a characteristic of preeclampsia. However, the potential molecular mechanisms of this condition remain obscure. The current study aimed to determine the direct effect of the peptide antigen corresponding to the second extracellular loop of the angiotensin II type 1 receptor (AT1R-EC(II) ) activating autoantibody (AT1-AA), a novel risk factor in preeclamptic patients, on fetoplacental villus stem blood vessels. Immunohistochemistry revealed that AT1 receptors were localized in the veins and arteries of human placental villi. Among 58 serum samples from preeclamptic patients, 28 (48.28%) were proved AT1-AA-positive by enzyme-linked immunosorbent assay [P<0.01 vs. 2/51 (3.92%) in the normal pregnancy group]. Total IgGs purified from AT1-AA-positive patients' sera (AT1-AA-IgGs) were added to isolated normal human placental blood vessels. The IgG significantly constricted both the villus veins and arteries in a dose-dependent manner in vitro, which could be blocked by the peptide corresponding to the human AT1R-EC(II) , anti-human IgG or the AT1 receptor antagonist losartan. Additionally, the venous constriction induced by AT1-AA-IgGs remained unchanged even at the end of the experiment (about half an hour), but the vasoconstriction caused by the AT1 receptor agonist angiotensin II underwent desensitization within three minutes. Collectively, our results demonstrated that AT1-AA in preeclamptic sera can directly constrict fetoplacental villus blood vessels without desensitization via the AT1 receptor in vitro, which might contribute to poor fetoplacental perfusion in preeclampsia.

Aim: To investigate the association between autoantibodies against angiotensin AT1 receptor (AT1-AAs) and endothelial dysfunction in vivo.Methods: Rat models with AT1 receptor antibodies (AT1-Abs) were established by active immunization for nine months. Lactate dehydrogenase (LDH) activity was regarded as an indicator of cell necrotic death. Endothelin-1 (ET-1) in the sera of rats was determined and endothelium-dependent vasodilatation was detected in isolated thoracic aorta. Endothelial intercellular adhesion molecule-1 (ICAM-1) expression in aorta endothelium was assessed using confocal microscopy. Coronary artery endothelial ultrastructure was observed. Results: IgGs in the immunized group significantly increased the LDH activity (0.84±0.17 vs 0.39±0.12, P<0.01 vs vehicle group IgGs) in incubated human umbilical vein endothelial cells through AT1 receptor. Higher content of ET-1 occurred in the immunized rats than that of the vehicle group, and reached two peaks at month 3 (27±4 ng/L, P<0.01) and month 7 (35±5 ng/L, P<0.01), respectively. In addition, aortic endothelium-dependent vasodilatation was attenuated; endothelial ICAM-1 level was markedly increased and cardiac capillary endothelium was damaged following immunization. Conclusion: Our study demonstrated that AT1-Abs contributed to endothelial dysfunction in vivo, which was a potential mechanism through which the antibodies play vital roles in related diseases.

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