The Effect Of Myeloid Differentiation Protein 1 On Ventricular Arrhythmias During Obesity Induced By High-fat Diet

Objective:Obesity is an important risk factor for ventricular arrhythmias(VAs).Myeloid differentiation protein 1(MD1)has been reported to decrease in the heart of obese mice,and improved the high-fat diets(HFD)-induced cardiac structural remodeling.However,the underlying mechanisms of MD1 in HFD-induced VAs have not been fully studied.The aim of our study was to investigate the role and mechanisms of MD1 in VAs caused by HFD.Methods and results:1.MD1 knock-out(MD1-KO)and wild type(WT)mice from experimental groups were fed with an HFD since the age of 6 weeks for 20 weeks.The biochemical and pathological analysis,echocardiography,electrocardiography,langendroff-perfused heart and molecular analysis were performed to detect HFD-induced vulnerability to VAs.Compared with normal diet(ND)mice,the HFD mice showed an increase in body weight,glucose intolerance,hyperlipidemia,QTc interval,left ventricular end-diastolic dimension(LVEDD)and left ventricular end-systolic dimension(LVESD).HFD feeding also increased vulnerability to VAs,as shown by the prolonged action potential duration(APD),enhanced APD alternans threshold and greater incident of VAs.Moreover,HFD feeding caused left ventricular(LV)hypertrophic and fibrosis,and decreased the protein and m RNA expressions of Kv4.2,Kv4.3,Kv1.5,Kv2.1 and Cav1.2.Finally,the above mentioned HFD-induced adverse effects were further exacerbated in MD-KO mice compared to WT mice.2.MD1-KO and WT mice from the experimental groups were fed with an HFD since the age of 6weeks for 20 weeks.The potential electrophysiological remodeling was estimated by whole-cell patch-clamp.Compared with ND-fed mice,APD from LV myocytes of HFD-fed mice showed a profoundly enlarged in APD₂₀,APD₅₀ and APD₉₀.Furthermore,HFD mice showed a decrease in the current density of fast transient outward potassium current(I_to,f)and slowly inactivating potassium current(I_K,slow),and no significantly change in non-inactivating steady-state outward potassium current(I_ss).Besides,HFD-fed mice showed a decrease in the current density of L-type calcium channel(LTCC)current(I_{Ca L}),and shifted right in the half inactivation voltage of LTCC.However,the half activation voltage and recovery time constant for LTCC was comparable in ND-fed and HFD-fed mice.These HFD induced above adverse effects in cardiomyocyte were further exacerbation in MD1-KO mice compared to WT mice.3.MD1-KO and WT mice from experimental groups were fed with an HFD since the age of 6 weeks for20 weeks.Adenovirus infection technique transfects Ad-sh MD1 to down-regulate the expression of MD1 in H9c2 cells,and then cultured H9c2 cells with free fatty acids(FFA).The potential mechanisms were estimated by molecular analysis.MD1 deletion markedly enhanced the activation of TLR4/My D88/Ca MKII signaling pathway in the HFD-fed mice and FFA-cultured H9c2 cells.Blocking Ca MKII with inhibitor(KN93)greatly attenuated the detrimental effects on MD1 knock-down H9c2 cells exposed to FFA.Conclusion:MD1 deficiency increased HFD-induced vulnerability to VAs.This is mainly caused by the aggravated maladaptive LV hypertrophy and fibrosis,and decreased expression of ion channels,as well as down-regulated potassium currents and slowed inactivation of LTCC,which are induced by the enhanced the activation of TLR4/My D88/Ca MKII signaling pathway.Therefore,MD1 may be an essential target for the prevention and treatment of obesity-induced VAs.