Targeting Transmembrane BAX Inhibitor Motif Containing 1 Alleviates Pathological Cardiac Hypertrophy

作者：Ke‐Qiong Deng, Guang‐Nian Zhao, Zhihua Wang, Jing Fang, Zhou Jiang, Jun Gong, Fengjuan Yan, Xue‐Yong Zhu, Peng Zhang, Zhi‐Gang She, Hongliang Li · 发表于：Circulation · 年份：2017 · DOI：10.1161/circulationaha.117.031659 · 被引用次数：58 · 研究领域：Cardiac Fibrosis and Remodeling、Cellular transport and secretion、Cell Adhesion Molecules Research

Background: 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 transmembrane BAX inhibitor motif containing 1 (TMBIM1) mRNA 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, and coimmunoprecipitation analyses to identify the downstream targets of TMBIM1 in cardiac hypertrophy. Tmbim1 / Tlr4 double-knockout mice were generated to investigate whether the effects of TMBIM1 on cardiac hypertrophy were Toll-like receptor 4 (TLR4) dependent. Finally, lentivirus-mediated TMBIM1 overexpression in a monkey AB model was performed to evaluate the therapeutic potential of TMBIM1. Results: TMBIM1 expression was significantly downregulated on 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...