Losartan prevents aortic dissection via downregulating TGF-β/SMADs pathway in Sprague Dawley rats

【摘要】 Background Aortic dissection(AD) is a lethal medical emergency, which lacks specific biomarkers and effective pharmaceutical therapies. Increasing evidences have shown beneficial effect of angiotensin receptor blocker(ARB) drugs on downregulating transforming growth factor-β(TGF-β) pathway in Marfanoid AD. However,for non-Marfanoid AD, the effectiveness of ARB drugs, as well as the possible mechanisms, remains unclear.Methods Sprague Dawley(SD) rats were fed by gavage(i.g.) with either 150 mg/(kg·d) Hydroxyethyl diamine(AEEA) or isovolumic saline(normal saline group). AEEA-induced SD rats were further randomly divided into three groups, including the AEEA+Losartan group [AEEA induction+20 mg/(kg·d) i.g. Losartan], the AEEA+Amlodipine group [AEEA induction + 6.5 mg/(kg · d) i.g. Amlodipine] and the AEEA + normal saline group(AEEA induction+isovolumic saline i.g.) group. Thus there were 4 groups with 12 mice in each. Tail blood pressure, aortic diameter and the number of aortic dissected lesions were measured in the above 4 groups 4 weeks thereafter. Western-blot was used to detect the expression of components of TGF-β/SMADs pathway, such as TGF-β1, drosophila mothers against decapentaplegic protein 2(Smad2), Smad3, Smad4, protein kinase B(AKT)and phosphorylated AKT(p-AKT). Results No significant difference of blood pressure was seen between the AEEA+Losartan group and the AEEA+Amlodipine group(P=0.81). Ultrasound data indicated a significant reduction in aortic dilation of ascending aorta, aortic arch and descending aorta in Losartan intervention group relative to the Amlodipine intervention group(P<0.001). Hematoxylin-eosin(HE) staining of aortic tissue demonstrated that under the setting of AEEA induction, AEEA+Losartan group had a lower incidence of aortic dissection than the AEEA+normal saline group and the AEEA+Amlodipine group(all P<0.01). Losartan significantly reduced the expression of TGF-β1, Smad2, Smad3, Smad4 in aortic tissues of AEEA-induced rats(all P<0.05). Conclusions Independent of BP reduction, Losartan, as an ARB drug, can prevent aortic dissection by inhibiting TGF-β/SMADs signaling pathway.[S Chin J Cardiol 2020;21(4):269-276]更多还原

【Abstract】 Background Aortic dissection(AD) is a lethal medical emergency, which lacks specific biomarkers and effective pharmaceutical therapies. Increasing evidences have shown beneficial effect of angiotensin receptor blocker(ARB) drugs on downregulating transforming growth factor-β(TGF-β) pathway in Marfanoid AD. However,for non-Marfanoid AD, the effectiveness of ARB drugs, as well as the possible mechanisms, remains unclear.Methods Sprague Dawley(SD) rats were fed by gavage(i.g.) with either 150 mg/(kg·d) Hydroxyethyl diamine(AEEA) or isovolumic saline(normal saline group). AEEA-induced SD rats were further randomly divided into three groups, including the AEEA+Losartan group [AEEA induction+20 mg/(kg·d) i.g. Losartan], the AEEA+Amlodipine group [AEEA induction + 6.5 mg/(kg · d) i.g. Amlodipine] and the AEEA + normal saline group(AEEA induction+isovolumic saline i.g.) group. Thus there were 4 groups with 12 mice in each. Tail blood pressure, aortic diameter and the number of aortic dissected lesions were measured in the above 4 groups 4 weeks thereafter. Western-blot was used to detect the expression of components of TGF-β/SMADs pathway, such as TGF-β1, drosophila mothers against decapentaplegic protein 2(Smad2), Smad3, Smad4, protein kinase B(AKT)and phosphorylated AKT(p-AKT). Results No significant difference of blood pressure was seen between the AEEA+Losartan group and the AEEA+Amlodipine group(P=0.81). Ultrasound data indicated a significant reduction in aortic dilation of ascending aorta, aortic arch and descending aorta in Losartan intervention group relative to the Amlodipine intervention group(P<0.001). Hematoxylin-eosin(HE) staining of aortic tissue demonstrated that under the setting of AEEA induction, AEEA+Losartan group had a lower incidence of aortic dissection than the AEEA+normal saline group and the AEEA+Amlodipine group(all P<0.01). Losartan significantly reduced the expression of TGF-β1, Smad2, Smad3, Smad4 in aortic tissues of AEEA-induced rats(all P<0.05). Conclusions Independent of BP reduction, Losartan, as an ARB drug, can prevent aortic dissection by inhibiting TGF-β/SMADs signaling pathway.[S Chin J Cardiol 2020;21(4):269-276]更多还原