Lysosomal-Associated Protein Transmembrane 5 Functions as a Novel Negative Regulator of Pathological Cardiac Hypertrophy.
Lysosomal-Associated Protein Transmembrane 5 Functions as a Novel Negative Regulator of Pathological Cardiac Hypertrophy.
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DOI：
10.3389/fcvm.2021.740526
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发表时间：
2021
影响因子：
3.6
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Gao L;Guo S;Long R;Xiao L;Yao R;Zheng X;Zhang Y;Wang X
溶酶体相关蛋白跨膜5（LAPTM 5）主要在免疫细胞中表达，并已被报道调节炎症、凋亡和自噬。尽管LAPTM 5在心脏中表达，但LAPTM 5是否在调节心脏功能方面发挥作用仍不清楚。在这里，我们表明，LAPTM 5的表达显着降低，在小鼠肥大的心脏和孤立的肥大心肌细胞。本研究旨在探讨LAPTM 5在病理性心肌肥厚中的作用及其可能机制。我们的研究结果表明，LAPTM 5基因缺失显著加剧心脏重塑，这可以通过减少心肌肥厚，纤维化，心室扩张和保留射血功能来证明，而在LAPTM 5过表达小鼠中观察到相反的表型。与体内结果一致，LAPTM 5的敲低加重了新生大鼠心室肌细胞中血管紧张素II诱导的心肌细胞肥大，而LAPTM 5的过表达在体外保护了血管紧张素II诱导的心肌细胞肥大。从机制上讲，LAPTM 5直接与Rac 1结合，并进一步抑制MEK-ERK 1/2信号传导，最终调节心脏肥大的发展。此外，LAPTM 5的抗肥大作用在很大程度上被组成型活性突变体Rac 1（G12 V）阻断。总之，我们的研究结果表明，LAPTM 5参与病理性心脏肥大，靶向LAPTM 5在治疗病理性心脏肥大方面具有巨大的治疗潜力。
Lysosomal-associated protein transmembrane 5 (LAPTM5) is mainly expressed in immune cells and has been reported to regulate inflammation, apoptosis and autophagy. Although LAPTM5 is expressed in the heart, whether LAPTM5 plays a role in regulating cardiac function remains unknown. Here, we show that the expression of LAPTM5 is dramatically decreased in murine hypertrophic hearts and isolated hypertrophic cardiomyocytes. In this study, we investigated the role of LAPTM5 in pathological cardiac hypertrophy and its possible mechanism. Our results show that LAPTM5 gene deletion significantly exacerbates cardiac remodeling, which can be demonstrated by reduced myocardial hypertrophy, fibrosis, ventricular dilation and preserved ejection function, whereas the opposite phenotype was observed in LAPTM5 overexpression mice. In line with the in vivo results, knockdown of LAPTM5 exaggerated angiotensin II-induced cardiomyocyte hypertrophy in neonatal rat ventricular myocytes, whereas overexpression of LAPTM5 protected against angiotensin II-induced cardiomyocyte hypertrophy in vitro. Mechanistically, LAPTM5 directly bound to Rac1 and further inhibited MEK-ERK1/2 signaling, which ultimately regulated the development of cardiac hypertrophy. In addition, the antihypertrophic effect of LAPTM5 was largely blocked by constitutively active mutant Rac1 (G12V). In conclusion, our results suggest that LAPTM5 is involved in pathological cardiac hypertrophy and that targeting LAPTM5 has great therapeutic potential in the treatment of pathological cardiac hypertrophy.