Loss of LSD1 ameliorates myocardial infarction by regulating angiogenesis via transcriptional activation of Vegfa

Abstract

Aims

Our study aims to explore the regulatory role and underlying mechanisms of Lysine-specific demethylase 1 (LSD1) in angiogenesis following myocardial infarction (MI).

Materials and methods

We generated inducible cardiomyocyte-specific Lsd1 knockout (Lsd1-cKO) mice and established a MI model. The function of LSD1 in cardiac angiogenesis in MI mice was assessed through echocardiography, histopathological staining, and immunofluorescence analysis. In vitro, Lsd1 silencing in cardiomyocytes was achieved by transfecting small interfering RNA (siRNA), followed by hypoxic treatment to simulate the in vivo MI model. The above cardiomyocyte-conditioned medium was collected and used to treat endothelial cells to observe changes in endothelial function. Additionally, we employed Cleavage Under Targets and Tagmentation sequencing (CUT&Tag-seq) to investigate the potential mechanisms by which LSD1 exerts its effects.

Key findings

We found that the absence of LSD1 protected against cardiac dysfunction and promoted angiogenesis in mice with MI. Lsd1-silenced cardiomyocytes enhance the migration and tube formation function of endothelial cells by releasing vascular endothelial growth factor A (VEGF-A) under hypoxic conditions. The combined analysis of CUT&Tag-seq data revealed that silencing of Lsd1 promoted the monomethylation of H3K4 at the Vegfa promoter and region, leading to the transcriptional activation of Vegfa mRNA in cardiomyocytes.

Significance

Our research indicates that lowered level of LSD1 in cardiomyocytes enhances VEGF-A paracrine secretion and improves endothelial cell function through cross-talk, ultimately promoting angiogenesis. These findings suggest that targeting LSD1 might be an effective therapeutic approach to protect against MI.