Gabapentin attenuates cardiac remodeling after myocardial infarction by inhibiting M1 macrophage polarization through the peroxisome proliferator-activated receptor-γ pathway

Abstract

ObjectivesInflammation regulates ventricular remodeling after myocardial infarction (MI), and gabapentin exerts anti-inflammatory effects. We investigated the anti-inflammatory role and mechanism of gabapentin after MI. MethodsRats were divided into the sham group (n = 12), MI group (n = 20), and MI + gabapentin group (n = 16). MI was induced by left coronary artery ligation. The effects of gabapentin on THP-1-derived macrophages were examined in vitro. ResultsIn vivo, 1 week after MI, gabapentin significantly reduced inducible nitric oxide synthase (iNOS; M1 macrophage marker) expression and decreased pro-inflammatory factors (tumor necrosis factor [TNF]-α and interleukin [IL]-1β). Gabapentin upregulated the M2 macrophage marker arginase-1, as well as CD163 expression, and increased the expression of anti-inflammatory factors, including chitinase-like 3, IL-10, and transforming growth factor-β. Four weeks after MI, cardiac function, infarct size, and cardiac fibrosis improved after gabapentin treatment. Gabapentin inhibited sympathetic nerve activity and decreased ventricular electrical instability in rats after MI. Tyrosine hydroxylase and growth-associated protein 43 were suppressed after gabapentin treatment. Gabapentin downregulated nerve growth factor (NGF) and reduced pro-inflammatory factors (iNOS, TNF-α, and IL-1β). In vitro, gabapentin reduced NGF, iNOS, TNF-α, and IL-1β expression in lipopolysaccharide-stimulated macrophages. Mechanistic studies revealed that the peroxisome proliferator-activated receptor-γ antagonist GW9662 attenuated the effects of gabapentin. Moreover, gabapentin reduced α2δ1 expression in the macrophage plasma membrane and reduced the calcium content of macrophages. ConclusionGabapentin attenuates cardiac remodeling by inhibiting inflammation via peroxisome proliferator-activated receptor-γ activation and preventing calcium overload.