Acacetin alleviates cardiac fibrosis via TGF-1/Smad and AKT/mTOR signal pathways in spontaneous hypertensive rats
Gerontology(2023)
摘要
Introduction: Attenuation of the activation of cardiac fibroblasts contributes to reduce the excessive extracellular matrix deposition and cardiac structural remodeling in hypertensive hearts. Acacetin has shown to play a protective role in doxorubicin-induced cardiomyopathy. The aim of this study was to investigate the potential molecular mechanisms underlying the protective role of acacetin on hypertension-induced fibrosis in the heart. Methods: Echocardiography, pathological morphological and western-blotting techniques were used to evaluate the anti-fibrosis effects in spontaneous hypertensive rat (SHR) which were daily intragastric administrated with acacetin (10mg/kg and 20mg/kg) for 6 weeks. Angiotensin II (Ang II) was used to induce cellular fibrosis in human cardiac fibroblasts in the absence and presence of acacetin treatment for 48 hours. Results: Acacetin alleviated hypertension-induced left ventricular posterior wall thickness and relieved cardiac remodeling in SHR. The expressions of collagen-1, collagen-III and alpha-SMA were remarkedly decreased after treatment with acacetin (n=6, P<0.05). The wound closure rate and the number of migratory cells per field were decreased by 3 and 10 & mu;mol/L acacetin in Ang II-treated fibroblasts (n=6, P < 0.05). Acacetin (10 & mu;mol/L) inhibited Ang II-induced upregulation of collagen-1 and collagen-III (n=6, P < 0.05), and downregulation of the expression of alpha-SMA reversed the differentiation of fibroblasts to myofibroblasts. Acacetin also decreased the expression of TGF-& beta;1, the fraction of p-Smad3/Smad3, and p-AKT and p-mTOR, but increased the expression of Smad7 (n=6, P < 0.05). Furthermore, acacetin inhibited TGF-& beta;1 agonist SRI and AKT agonist SC79 caused fibrotic effect. Conclusion: In summary, acacetin inhibits the hypertension-associated cardiac fibrotic processes through regulating TGF-& beta;/Smad3, AKT/mTOR signal transduction pathways.
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