Lysosomal-Associated Protein Transmembrane 5 Functions as a Novel Negative Regulator of Pathological Cardiac Hypertrophy

Abstract

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.

Suppression of lysosomal-associated protein transmembrane 5 ameliorates cardiac function and inflammatory response by inhibiting the nuclear factor-kappa B (NF-κB) pathway after myocardial infarction in mice

“…concluded that LAPTM5 was involved in pathological cardiac hypertrophy and LAPTM5 deletion aggravated pressure load-induced myocardial hypertrophy and heart failure through MEK-ERK1/2 pathway in mice, as evidenced by changed echocardiographic parameters [14]. We analyze that different animal models, disease duration, and signaling pathways involved are the reasons for the differential role of LAPTM5 in the heart diseases.…”

“…Our result showed that the inhibition of LAPTM5 could suppress the enhancement of MCP-1 and CD86 caused by MI. However, except for macrophages, LAPTM5 was also shown to be present in cardiomyocytes, indicating its widespread expression [14]. We speculated that the mechanism of LAPTM5 knockdown alleviating MI might be associated with a variety of cells.…”

“…It has been confirmed that it participates in the degradation of phagosomes through the lysosomal pathway and is related to cell apoptosis and its clearance [10,11]. Besides that, some researchers have found that LAPTM5 is engaged in some signaling pathways regulation, containing NF-kB, TGFb-Smads, MEK-ERK1/2, PI3K-AKT, and MAPKs, which are related to cardiovascular diseases [12][13][14]. These studies suggest that LAPTM5 may play an important role in cardiovascular disease, while, the role of LAPTM5 in MI is not clear.…”

Lysosomal-associated transmembrane protein 5 deficiency exacerbates cerebral ischemia/reperfusion injury

“…In CD40 positive glioblastoma, LAPTM5 expression could suppress tumor growth by inhibiting CD40-mediated activation of NF-κB ( Berberich et al, 2020 ). Furthermore, LAPTM5 could play an important protective role in pathological myocardial hypertrophy through the Rac1-MEK-ERK1/2 pathway ( Gao et al, 2021 ). On the other hand, in some previous studies, LAPTM5 has been shown to negatively regulate cell survival.…”

Lysosomal-Associated Transmembrane Protein 5 Promotes Proliferation, Migration, and Invasion of Clear Cell Renal Cell Carcinoma

“…As a lysosomal transmembrane protein, LAPTM5 is widely involved in various cell functions, including protein transport, immune cell activation, signal pathway activation, autophagy, and oxidative stress [9,[15][16][17][18][19][20]. LAPTM5 is also widely involved in the progression of various cellular activities and signaling pathways.…”