The Role Of Myeloid Differentiation 1 In Pathological Cardiac Remodelling And Its Mechanism

Objective:Myeloid Differentiation 1(MD-1),a secreted protein interacting with radioprotective 105(RP105),plays an important role in Toll-like receptor 4(TLR4)signaling pathway.Previous studies showed that MD-1 may be restricted in the immune system and involved in the differentiation of immune cells.In this study,we reported for the first time that MD-1 was also highly expressed in both human and animal hearts.Given that TLR4 has been found to be involved in the development of pathological cardiac hypertrophy,we then ask whether MD-1,as an inhibitor of the TLR4 signaling pathway,plays a critical role in pressure overload-induced cardiac remodeling.We therefore investigated the role of MD-1 in cardiac remodelling and the mechanisms underlying its activity.Methods and results:We used western blot analysis to show that MD-1 was down-regulated in human failing hearts and murine hypertrophic hearts.The global MD-1-knockout mice were utilized to investigate the role of MD-1 in murine hearts in response to chronic aortic banding(AB).The results of echocardiography,immunohistochemistry,and molecular/biochemical analyses showed that the global MD-1-knockout mice exaggerates cardiac hypertrophy,fibrosis,and dysfunction.We then used cultured neonatal rat cardiomyocytes to demonstrate that inducing the adenovirus vector-mediated overexpression of MD-1 attenuated angiotensin II-induced cell hypertrophy,whereas knocking down MD-1 using shRNA exerted opposite effects.Furthermore,we found that the antihypertrophic effects of MD-1 under hypertrophic stimuli were associated with the blockage of MEK-ERK 1/2 and NF-K B signaling.Blocking MEK-ERK 1/2 signaling with a pharmacological inhibitor(U0126)greatly reversed the detrimental effects observed in MD-1 k:nockout cardiomyocyte subjected to angiotensin II stimuli.Similar results were observed for Blocking NF-κ B signaling with a pharmacological inhibitor(BAY11-7082).Conclusion:Our results demonstrate that MD-1 inhibits cardiac hypertrophy and postpones cardiac dysfunction during the remodeling process,which is dependent on its modulation of the MEK-ERK 1/2 and NF-κ B signaling axis.Thus,MD-1 might be a novel target for the treatment of pathological cardiac hypertrophy and failure.