Abstract
Aim: The study aims to evaluate protective effects of sophoricoside (Sop) on cardiac hypertrophy. Meanwhile, the potential and significance of Sop should be broadened and it should be considered as an attractive drug for the treatment of pathological cardiac hypertrophy and heart failure.Methods: Using the phenylephrine (PE)-induced neonatal rat cardiomyocytes (NRCMs) enlargement model, the potent protection of Sop against cardiomyocytes enlargement was evaluated. The function of Sop was validated in mice received transverse aortic coarctation (TAC) or sham surgery. At 1 week after TAC surgery, mice were treated with Sop for the following 4 weeks, the hearts were harvested after echocardiography examination.Results: Our study revealed that Sop significantly mitigated TAC-induced heart dysfunction, cardiomyocyte hypertrophy and cardiac fibrosis. Mechanistically, Sop treatment induced a remarkable activation of AMPK/mTORC1-autophagy cascade following sustained hypertrophic stimulation. Importantly, the protective effect of Sop was largely abolished by the AMPKα inhibitor Compound C, suggesting an AMPK activation-dependent manner of Sop function on suppressing pathological cardiac hypertrophy.Conclusion: Sop ameliorates cardiac hypertrophy by activating AMPK/mTORC1-mediated autophagy. Hence, Sop might be an attractive candidate for the treatment of pathological cardiac hypertrophy and heart failure.
Highlights
Heart failure is defined as the inability of heart to supply the peripheral tissues with the required amount of blood and oxygen to meet their metabolic demands, and is an epidemic disease in the modern world affecting approximately 1–2% of adult population [1]
Immunofluorescence staining showed that Sop at different concentrations (10, 20, 50 μM) had no effect on cardiac hypertrophy (Supplementary Figure S1A,B), the mRNA levels of cardiac markers A-type natriuretic peptide (Anp), myosin heavy chain 7 (Myh7)) had no changes after Sop treatment (Supplementary Figure S1C)
Results showed that PE induced a dramatic enlargement of neonatal rat cardiomyocyte (NRCM), which was effectively alleviated by treatment with Sop, as supported by quantified cell surface area and measurement of cell length and width of NRCMs (Figure 1A,B)
Summary
Heart failure is defined as the inability of heart to supply the peripheral tissues with the required amount of blood and oxygen to meet their metabolic demands, and is an epidemic disease in the modern world affecting approximately 1–2% of adult population [1]. Heart failure is a syndrome with symptoms and signs caused by cardiac dysfunction, resulting in reduced longevity [2]. Heart failure is usually accompanied by cardiac hypertrophy and fibrosis [3]. Under numerous hypertrophic stimuli, such as chronic inflammatory response, pressure overload, ischemia, valvular heart disease and excess neurohormonal activation, cardiac hypertrophy eventually develops into maladaptive cardiac remodeling and heart failure [4]. The main pathological features of cardiac hypertrophy includes cardiomyocyte enlargement, overexpression of fetal genes, protein synthesis increase, myocardial fibrosis, cell signal dysfunction and autophagy inhibition [5,6]. A great deal of signaling pathways have been well validated in the progression of cardiac hypertrophy [7]. Pharmacological therapies that modulate these signaling pathways might embody great promise for treating pathological cardiac hypertrophy
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