The Role And Mechanism Of TMBIM1 On Pathological Cardiac Hypertrophy

Background: Pathological cardiac hypertrophy and its resultant heart failure are among the most common causes of mortality worldwide.Abnormal protein degradation,especially the impaired lysosomal degradation of large organelles and membrane proteins,is involved in the progression of cardiac hypertrophy.However,the underlying mechanisms have not been fully elucidated.Methods:We investigated cardiac TMBIM1 m RNA and protein expression levels in samples from patients with heart failure and mice with aortic banding(AB)-induced cardiac hypertrophy.We generated cardiac-specific Tmbim1 knockout mice and cardiac-specific Tmbim1-overexpressing transgenic mice and then challenged them with AB surgery.We used microarray,confocal image,co-immunoprecipitation analyses to identify the downstream targets of TMBIM1 in cardiac hypertrophy.Tmbim1/Tlr4 double knockout(DKO)mice were generated to investigate whether the effects of TMBIM1 on cardiac hypertrophy were TLR4 dependent.Finally,lentivirusmediated TMBIM1 overexpression in monkey AB model was performed to evaluate the therapeutic potential of TMBIM1.Results: TMBIM1 expression was significantly downregulated upon hypertrophic stimuli in both human and mice heart samples.Silencing cardiac Tmbim1 aggravated AB-induced cardiac hypertrophy.This effect was blunted by Tmbim1 overexpression.Transcriptome profiling revealed that the TLR4 signaling pathway was disrupted dramatically by manipulating Tmbim1.The effects of TMBIM1 on cardiac hypertrophy were shown to be dependent on TLR4 in DKO mice.Fluorescent staining indicated that TMBIM1 promoted the lysosome-mediated degradation of activated TLR4.Coimmunoprecipitation assays confirmed that TMBIM1 directly interacted with TSG101 via a PTAP motif and accelerated the formation of multivesicular bodies(MVBs)that delivered TLR4 to the lysosomes.Finally,lentivirus-mediated TMBIM1 overexpression reversed AB-induced cardiac hypertrophy in monkeys.Conclusions: TMBIM1 protects against pathological cardiac hypertrophy through promoting the lysosomal degradation of activated TLR4.Our findings reveal the central role of TMBIM1 as a MVB regulator in the progression of pathological cardiac hypertrophy,as well as the role of vesicle trafficking in signaling regulation during cardiac hypertrophy.Moreover,targeting TMBIM1-TLR4 axis could be a novel therapeutic strategy for treating cardiac hypertrophy and heart failure.