Resveratrol prevents ISO-induced myocardial remodeling associated with regulating polarization of macrophages through VEGF-B/AMPK/NF-kB pathway

Macrophage expansion and inflammatory responses are involved in induction of cardiac remodeling. Resveratrol has strong anti-inflammatory effects, however its effect on macrophage infiltration and polarization is unknown. This study aimed to investigate the anti-inflammatory effects of RSV on ISO-induced myocardial remodeling in mice and its regulatory role in macrophage polarization. BALB/c mice were orally administered with RSV (100 mg/kg) daily for one week, then were subcutaneously injected with ISO (50 mg/kg) daily for another week. ISO injections to mouse caused cardiac dysfunction evidenced by cardiac hypertrophy and cardiomyocyte fibrosis. Meanwhile, macrophage M1 polarization was found in ISO treated mice, which was evidenced by increased percentage of Ly6Clow macrophages in the heart, levels of M1 cytokines and expression of CD68, and decreased percentage of Ly6Chigh macrophage, levels of M2 cytokines and expression of CD206. All these changes in cardiac and macrophage M1 polarization were ameliorated when mice were pretreated with RSV. The effect of RSV on macrophage polarization was also tested in RAW264.7 cells. It was found that pre-treatment with RSV decreased the levels of M1 marker or proinflammatory cytokines, while increased the levels of M2 markers in ISO treated cells. In addition, it was found that RSV could upregulate the expression of VEGF-B and the activity of AMPK, while it downregulated the expression of phosphorylated NF-κB p65 both in RAW264.7 cells and in mice. Furthermore, pretreatment with VEGF-B siRNA greatly reversed changes in almost all above parameters evoked by RSV in RAW264.7 cells. Therefore, our findings suggest RSV has potential therapeutic effects in ISO-induced myocardial injury, which may be by inhibiting the M1 polarization of macrophages through VEGFB/AMPK/NF-кB pathway.