Author + information
- Xia Yunlong,
- Fuyang Zhang,
- Wenjun Yan,
- Shihao Zhao,
- Wei Wang and
- Ling Tao
Heart failure may develop insidiously years later after an acute myocardial infarction (AMI), despite the absence of ongoing ischemia. It is a staggering clinical and public health problem, associated with significant mortality, morbidity, and healthcare expenditures. So it is of urgent necessity to develop new targets to improve the prognosis of heart failure. Farnesyl X Receptor (FXR) is an endogenous bile acid receptor, belonging to the nuclear receptor superfamily, and it is also an important nuclear transcription factor. Recent studies have found that FXR is highly expressed in cardiomyocytes. During myocardial ischemia-reperfusion injury, myocardial FXR is up-regulated and promotes cardiomyocyte apoptosis. But there is still no relevant report about the role of FXR in myocardial infarction (MI). This project aims to identify the role of FXR in post-MI heart failure.
Forty-eight adult male C57BL/6J mice were randomly subjected to sham or permanent MI and divided into the following groups: sham+vehicle, MI+vehicle, sham+GW4064 (a specific agonist of FXR), MI+GW4064. At 24h after MI, GW4064 was administered by gavage (25mg/kg/d) for 3 weeks. After 3 weeks, Myocardial FXR expression and small heterodimer partner (SHP, a downstream molecule of FXR) mRNA levels were examined by Western blot and real-time PCR respectively to determine the transcriptional activity of myocardial FXR. Echocardiography was performed to assess cardiac function. Masson-trichrome staining, myocardial ANP and BNP (remodeling marker genes) mRNA levels, myocardial MMP9 protein and mRNA levels were used to evaluate cardiac remodeling and fibrosis. In vitro study used cardiomyocytes and cardiac fibroblasts isolated from neonatal Sprague-Dawley rats. After administration of 0mM, 0.1mM, 0.5mM and 1mM GW4064 for 10 hours, MMP9 protein and mRNA levels were determined.
At 3 weeks after MI, myocardial FXR expression was downregulated. Transcriptional activity of FXR was also remarkably impaired as evidenced by reduced SHP mRNA level. GW4064 administration restored FXR transcriptional activity and significantly improved cardiac function (LVEF: 35.5±3.0% vs. 29.4±2.7%, MI+GW4064 group vs. MI+Vehicle group, P<0.05) after MI. GW4064 remarkably reduced myocardial ANP and BNP mRNA levels, and lowered myocardial MMP9 protein and mRNA levels after MI, together with ameliorated myocardial fibrosis, demonstrating that GW4064 attenuated cardiac remodeling. In vitro study showed that GW4064 could dose-dependently reduce MMP9 protein and mRNA levels in cardiomyocytes and fibroblasts.
GW4064 administration notably ameliorated post-MI cardiac dysfunction and remodeling. This study for the first time demonstrates that FXR may be a potential therapeutic target in post-MI heart failure.