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Cardiac fibrosis is a common characteristic of many cardiac diseases. Our previous results showed that TRPM7 channel played an important role in the fibrosis process. MicroRNA-135a was reported to get involved in the fibrotic process. Astragalus membranaceus (Fisch.) Bunge was widely used in Chinese traditional medicine and showed cardiac protective effects in previous researches. Astragaloside IV(ASG), which is regarded as the most important ingredient of Astragalus, has been showed the effect of cardiac protection via various mechanisms, while no data suggested its action related to miRNAs regulation. The objective of this article is to investigate the inhibition effect of ASG on cardiac fibrosis through the miR-135a-TRPM7-TGF-β/Smads pathway. We extracted the active components from herb according to the paper and measured the content of ASG from the mixture via HPLC. The inhibition potency of cardiac hypertrophy between total extract of Astragalus and ASG was compared. SD rats were treated with ISO (5 mg/kg/day) subcutaneously (s.c.) for 14 days, ASG (10 mg/kg/d) and Astragalus extract (AE) (4.35 g/kg/d, which contained about ASG 10 mg) were given p.o. from the 6th day of the modeling. Cardiac fibroblasts (CFs) of neonatal rats were incubated with ISO (10 μM) and treated with ASG (10 μM) simultaneously for 24 h. The results showed that both AE and ASG treatment reduced the TRPM7 expression from the gene level and inhibited cardiac fibrosis. ASG group showed similar potency as the AE mixture. ASG treatment significantly decreased the current, mRNA and protein expression of TRPM7 which was one of targets of miR-135a. The activation of TGF-β/Smads pathway was suppressed and the expression of α-SMA and Collagen I were also decreased obviously. In addition, our results showed that there was a positive feedback between the activation of TGF-β/Smads pathway and the elevation of TRPM7, both of which could promote the development of myocardial fibrosis. AE had the effect of cardiac fibrosis inhibition and decreased the mRNA expression of TRPM7. ASG, as one of the effective ingredients of AE, showed the same potency when given the same dose. ASG inhibited cardiac fibrosis by targeting the miR-135a-TRPM7-TGF-β/Smads pathway. Image 1 [ABSTRACT FROM AUTHOR]

Background: Cancer patients receiving anthracycline-based chemotherapy (Anth-bC) may experience early cardiac fibrosis, which could be an important contributing mechanism to the development of impaired left ventricular (LV) function. Substance P, a neuropeptide that predominantly acts via the neurokinin 1 receptor (NK-1R), contributes to adverse myocardial remodelling and fibrosis in other cardiomyopathies. We sought to determine if NK-1R blockade is effective against doxorubicin (Dox - a frequently used Anth-bC)-induced cardiac fibrosis and cardiomyocyte apoptosis. In addition, we explored the direct effects of Dox on cardiac fibroblasts.Methods: Male Sprague-Dawley rats were randomised to receive saline, six cycles of Dox (1.5mg Dox/kg/cycle) or Dox with an NK-1R antagonist (L732138, 5mg/kg/daily through Dox treatment). At 8 weeks after the initial dose of Dox, LV function and histopathological myocardial fibrosis and cell apoptosis were assessed. Collagen secretion was measured in vitro to test direct Dox activation of cardiac fibroblasts.Results: Rats undergoing Dox treatment (9mg/kg cumulative dose) developed cardiac fibrosis and cardiomyocyte apoptosis. NK-1R blockade partially mitigated cardiac fibrosis while completely preventing cardiomyocyte apoptosis. This resulted in improved diastolic function. Furthermore, we found that Dox had direct effects on cardiac fibroblasts to cause increased collagen production and enhanced cell survival.Conclusions: This study demonstrates that cardiac fibrosis induced by Anth-bC can be reduced by NK-1R blockade. The residual fibrotic response is likely due to direct Dox effects on cardiac fibroblasts to produce collagen. [ABSTRACT FROM AUTHOR]