Edaravone inhibits pressure overload-induced cardiac fibrosis and dysfunction by reducing expression of angiotensin II AT1 receptor

Abstract

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.

Gallic acid improves cardiac dysfunction and fibrosis in pressure overload-induced heart failure

“…In the current study, the regulatory mechanism by which gallic acid reduces fibrosis may be attributed to the reduction of Smad3 protein levels induced by TAC. This result is consistent with a previous report that the protein level of Smad3 was increased at week 8 after TAC 35 .…”

Salvianolic Acid B-Alleviated Angiotensin II Induces Cardiac Fibrosis by Suppressing NF-κB Pathway In Vitro

“…It is becoming a global health burden and is still the leading cause of morbidity and mortality worldwide [ 22 , 23 ]. Cardiac fibrosis develops in pathological changes to various CVDs, including persisting hypertension, hypertropic cardiomyopathy, ischemic insults, and congenital heart defects [ 24 , 25 ]. Cardiac fibrosis is characterized by accumulation of cardiac fibroblasts (CFBs) and excessive deposition of extracellular matrix (ECM) [ 26 ].…”

Morphological and Functional Characteristics of Animal Models of Myocardial Fibrosis Induced by Pressure Overload

“…Some researchers confirmed the development of myocardial fibrosis in rats could be achieved by ligating the transverse aorta with 18-gauge needle and 4-0 silk suture for 8 weeks [15]. Its mortality rate and the success rate of the model were 7.14% and 85.71%, respectively [15]. Also myocardial fibrosis can be achieved with 17-gauge needle and 6-0 silk suture at the same observation time [16].…”

“…At present, there are different opinions about the establishment of this model. Some researchers confirmed the development of myocardial fibrosis in rats could be achieved by ligating the transverse aorta with 18-gauge needle and 4-0 silk suture for 8 weeks [15]. Its mortality rate and the success rate of the model were 7.14% and 85.71%, respectively [15].…”

“…Transverse aortic constriction model mainly elevates the afterload by ligating the aortic arch, then resulting in left ventricular hypertrophy and tissue remodeling, which is characterized by increased diameter of myocardial myocytes, accumulation of intercellular collagen, and left ventricular function impairment, ultimately leading to heart failure and death [14]. At the molecular level, the increase of blood pressure is related to Ang II AT 1 receptor activation [15].…”