Abstract
Cardiac hypertrophy and fibrosis are major pathophysiologic disorders that lead to serious cardiovascular diseases (CVDs), such as heart failure and arrhythmia. It is well known that transforming growth factor β (TGFβ) signaling pathways play a major role in the proliferation of cardiac hypertrophy and fibrosis, which is mainly stimulated by angiotensin II (AgII). This study aimed to investigate the cardioprotective potential of isorhamnetin (ISO) in human amniotic epithelial stem cells (hAESCs) through global gene expression analysis and to confirm its beneficial effects on cardiac hypertrophy and fibrosis in the AgII-induced in vivo model. In vitro, biological processes including TGFβ, collagen-related functions, and inflammatory processes were significantly suppressed in ISO pretreated hAESCs. In vivo, continuous AgII infusion using an osmotic pump induced significant pathological fibrosis and myocardial hypertrophy, which were remarkably suppressed by ISO pretreatment. ISO was found to reverse the enhanced TGFβ and Collagen type I alpha 1 mRNA expression induced by AgII exposure, which causes cardiovascular remodeling in ventricular tissue. These findings indicate that ISO could be a potential agent against cardiac hypertrophy and fibrosis.
Highlights
Pathological cardiac fibrosis is a fundamental process in the excessive accumulation of extracellular matrix (ECM) such as collagen (Travers et al, 2016), which plays a key role in the disruption of the myocardial architecture, myocardial disarray, and electrical and mechanical cardiomyocyte dysfunction (Izawa et al, 2005)
This study aimed to investigate the cardioprotective potential of ISO in human amniotic epithelial stem cells (hAESCs) through global gene expression analysis and to observe its effect on angiotensin II (AgII)-induced fibrosis and hypertrophy in the myocardium of mice
A total of 1210 unique genes were differentially expressed in ISO-treated hAESCs compared to untreated controls at day 10 (D10)
Summary
Pathological cardiac fibrosis is a fundamental process in the excessive accumulation of extracellular matrix (ECM) such as collagen (Travers et al, 2016), which plays a key role in the disruption of the myocardial architecture, myocardial disarray, and electrical and mechanical cardiomyocyte dysfunction (Izawa et al, 2005). In recent years, increasing numbers of small molecules derived from or based on bioactive compounds of medicinal plants have been synthesized and screened for their potential therapeutic and preventive effects in CVD. Physiologically more relevant in vitro human models for screening and validation of thousands of compounds are in high demand in both academic research and the pharmaceutical industry. In this context, stem-cell-based approaches using human pluripotent stem cells, including both human embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC), have received great attention as effective tools for drug screening, for CVDs and for other metabolic and neuronal diseases (Grskovic et al, 2011; Engle and Puppala, 2013). Cell resources, ethical constraints, invasive extraction procedures, and expensive cell reprogramming and maintenance procedures make this type of stem cell less favorable as a practical source for drug screening (Chen et al, 2014)
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