Abstract
Pressure overload leads to a hypertrophic milieu that produces deleterious cardiac dysfunction. Inflammation is a key pathophysiological mechanism underpinning myocardial hypertrophy. DL-3-n-butylphthalide (NBP), a neuroprotective agent, also has potent cardioprotective effects. In this study, the potential of NBP to antagonize myocardial hypertrophy was evaluated in C57BL/6 mice in vivo and in rat primary cardiomyocytes in vitro. In mice, NBP treatment reduced cardiac hypertrophy and dysfunction in a transverse aortic constriction (TAC)-induced pressure overload model. In angiotensin (Ang) II-challenged cardiomyocytes, NBP prevents cell size increases and inhibits gasdermin D (GSDMD)-mediated inflammation. Furthermore, overexpression of GSDMD-N reduced the protective effects of NBP against Ang II-induced changes. Using molecular docking and MD simulation, we found that the GSDMD-N protein may be a target of NBP. Our study shows that NBP attenuates myocardial hypertrophy by targeting GSDMD and inhibiting GSDMD-mediated inflammation.
Highlights
Hypertensive heart disease is characterized by adverse ventricular hypertrophy and cardiac dysfunction, leading to heart failure (Weber and Brilla, 1991)
These results indicated that NBP prevents TACinduced myocardial hypertrophy in vivo
This study showed that NBP, which was approved for ischaemic stroke by the State Food and Drug Administration in China in 2002, provides protection against pressure overload-mediated deleterious myocardial hypertrophy by directly binding to gasdermin D (GSDMD)-N protein and reducing GSDMD-mediated inflammation (Figure 5E)
Summary
Hypertensive heart disease is characterized by adverse ventricular hypertrophy and cardiac dysfunction, leading to heart failure (Weber and Brilla, 1991). Experimental and clinical studies have reported that the inflammatory response plays an important role in myocardial hypertrophy (Freund et al, 2005). Pressure overload induces an inflammatory myocardium phenotype (Sriramula et al, 2008). One investigation showed that IL-1β and the NLRP3 inflammasome play an important role in pressure overload-induced cardiac hypertrophy in mice (Sano et al, 2018). Suppressing IL-1β and the inflammasome pathway ameliorates transverse aortic constriction (TAC) -induced ventricular hypertrophy (Zhou et al, 2020). Anti-inflammatory therapy can be regarded as an important method to prevent cardiac hypertrophy
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