Pinoresinol diglucoside alleviates pressure overload-induced cardiac injury via the AMPK/SIRT3/RIG-1 pathway

AbstractAims Heart failure (HF) often results from mechanical or neurohormonal stress and remains the mortality up to 45–50%, which is accompanied by cardiomyocytes loss, apoptosis, and fibrosis. Pinoresinol diglucoside (PDG), a compound obtained from withForsythia suspensa,Epicommia ulmoidesandStyrax sp., has a remarkable effect on anti-hypertension, anti-inflammation and anti-oxidative stress. However, whether PDG protects against pressure overload induced cardiomyocytes fibrosis, apoptosis and oxidative stress has not been illustrated. This study aimed to determine the cardioprotective effects and the underlying mechanism of PDG on cardiomyocytes injury in pressure overload-induced rats. Methods Abdominal aortic constriction (AAC)-surgery was performed to mimic pressure overload-induced cardiac injury (fibrosis, apoptosis, oxidative stress, and inflammation) in rats. The collagen content deposit evaluation of heart in rats were evaluated by PSR staining. Furthermore, phenylephrine (PE) was used to make in vitro cell models of cardiac injury. We used quantitative real-time PCR (qRT-PCR) to test the expression of targeting mRNAs bothin vivoandvitro. Western blot assay was used to detect the protein expressions of the AMPK/SIRT3/RIG-1 signaling pathway. Results AAC induced the significant cardiac injury in hearts of rats, as indicators of myocytes fibrosis, apoptosis, oxidative stress and inflammation, whereas PDG treatment reversed these pathological changes compared to AAC rats. Moreover, AAC-induced increased left ventricular (LV) fibrosis, apoptosis, oxidative stress and inflammation compared to the Sham mice, but these increases were significantly reduced by PDG treatment. Interestingly, PDG in AAC-induced rats decreased the expressions of p-AMPK and SIRT3 at the protein levels. These results of this cardio-protection are likely through targeting cardiomyocytes fibrosis, apoptosis, oxidative stress and inflammation, possibly mediated by AMPK and SIRT3. In addition, PDG also blocked PE-induced the fibrotic changes in cardiomyocytes. Thus, PDG may be a potential therapeutic agent in targeting pathological cardiac injury by inhibiting myocytes fibrosis, apoptosis, oxidative stress and inflammation in pressure overload-induced cardiac injury. Conclusions PDG significantly decreased AAC-induced cardiomyocytes fibrosis, apoptosis, oxidative stress and inflammation in rats through the AMPK/SIRT3/RIG-1 signaling pathway. These novel findings provide the evidence that PDG may be a promising therapeutic strategy for pathological cardiac remodeling and HF.