The Role Of Myeloid Differentiation 1 In Obesity-induced Left Ventricle Remodelling And Its Mechanism

Objective: Myeloid differentiation protein 1(MD-1)interacting with radioprotective 105(RP105),could negative regulate Toll-like receptor 4(TLR4)signalling pathway.Previous studies showed that TLR4 was involved in the development of pathological cardiac remodelling.In our study,we reported that MD-1 was also highly expressed in both high-fat diet-induced obese mice and free fatty acid(FFA)-cultured H9C2 cells.We know little about whether MD-1 plays an important role in left ventricle remodelling resulting from high-fat diet-induced obese or free fatty acid intervention.What is the mechanism involved in left ventricle remodelling above? Therefore,we investigated the role of MD-1 in cardiac remodelling and the mechanisms underlying its activity.Methods and results: Using western blot analysis,we showed that MD-1 was down-regulated in both high-fat diet-induced obese mice and free fatty acid-cultured H9C2 cells.The global MD-1-knockout and MD-1-transgenic mice were utilized to evaluate the role of MD-1 in left ventricle remodeling in murine responsing to high-fat diet-induced obese.The results of echocardiography,biomedical analyzer,histopathological examination and molecular/biochemical analyses showed that the global MD-1-knockout mice and MD-1-transgenic mice exaggerated and attenuated left ventricle remodelling and dysfunction,respectively.Using FFA cultured H9C2 cells inducing the adenovirus vector-mediated silent-expression and overexpression of MD-1,the results of immunohistochemistry,cytopathology examination and molecular/biochemical analyses showed that FFA caused lipid deposition in cardiomyocytes,proliferation promotion and increased MD-1 protein expression.MD-1 silencing using sh RNA deteriorated FFA-induced cell remodelling,whereas overexpression of MD-1 exerted an opposite effect.Moreover,we demonstrated that against or deteriorated cardiac remodelling effects of MD-1 under obesity stimuli in vivo were related to the blockage of mitogen-activated protein kinases(MAPKs)and nuclear factor kappa B(NF-?B)signalling.Blocking mitochondrial extracellular signal-regulated kinase(MEK)-extracellular signal-regulated kinase(ERK)1/2 signalling with inhibitor(U0126)and NF-?B signalling with inhibitor(BAY11-7082),which interacted with each other,greatly attenuated the detrimental effects on MD-1 knockout cardiomyocyte exposed to FFA in vitro.Conclusion: Our results show that MD-1 attenuates left ventricle remodelling and dysfunction in high-fat diet-induced obesity or high FFA,which is dependent on its modulation of the MAPKs and NF-?B signalling pathway.Thus,MD-1 might be a novel target for the treatment of obesity-induced cardiac remodelling and failure.