Myofibroblast Deficiency of LSD1 Alleviates TAC-Induced Heart Failure

Abstract

Rationale: Histone lysine specific demethylase 1 (LSD1) is an important epigenetic anti-tumor drug target, whose inhibitors are currently in phase Ⅰ/Ⅱ clinical trials. However, the potential side effects of LSD1 inhibition in the progress of cardiac remodeling to heart failure remain to be investigated. Objective: To evaluate the roles of myofibroblast- or cardiomyocyte-specific LSD1 deficiency in pressure overload-induced cardiac remodeling. Methods and Results: Adult mouse cardiac fibroblasts (CFs)，neonatal rat cardiac myocytes (NRCMs) and fibroblasts (NRCFs) were isolated, respectively. The myofibroblast-specific and cardiomyocyte-specific LSD1 inducible knockout mice were then generated. We found that LSD1 was increased not only in human DCM (dilated cardiomyopathy) hearts, but also in wild type mouse heart homogenates and isolated CFs, following 20 weeks of transverse aortic constriction (TAC). The upregulation of LSD1 was also observed in Ang II-treated NRCFs, which was reversed by LSD1 silence or its activity inhibition by ORY-1001. These findings suggested a potential involvement of LSD1 in cardiac remodeling. Importantly, myofibroblast-specific LSD1 inducible knockout in vivo significantly alleviated systolic dysfunction, cardiac hypertrophy and fibrosis, following 6 and 20 weeks of TAC. Mechanistically, through RNA-sequencing and the following western blot analysis, we found that loss of LSD1 in Ang II-induced myofibroblasts not only inhibited the intracellular upregulation of transforming growth factor β1 (TGFβ1), its downstream effectors Smad2/3 phosphorylation, as well as the phosphorylation of p38, ERK1/2 and JNK, but also reduced the supernatant TGFβ1 secretion, which then decreased myocyte hypertrophy in the indirect co-culture model. On the other hand, cardiomyocyte-specific LSD1 inducible knockout in vivo triggered the reprogramming of fetal genes, mild cardiac hypertrophy and dysfunction under both basal and stressed conditions. Conclusions: Our findings, for the first time, implicate that myofibroblast-specific LSD1 deletion attenuates TAC-induced cardiac remodeling and improves heart function, suggesting that LSD1 is a potential therapeutic target for late stage heart failure.

Pyruvate Kinase M2 Protects Heart from Pressure Overload‐Induced Heart Failure by Phosphorylating RAC1

“…For picrosirius red staining, heart sections were incubated with picrosirius red solution (Abcam, ab150681) at RT for 1 hour as described previously. 26 Four to five randomly selected fields (magnification, ×200) were examined for collagen volume fraction analysis.…”

Targeting lysine‐specific demethylase 1A inhibits renal epithelial–mesenchymal transition and attenuates renal fibrosis

“…34 LSD1 inhibition has been reported to reduce the supernatant TGFβ1 secretion in Ang II-induced cardiac myofibroblasts, implying the possible involvement of LSD1 in TGFβrelated fibrotic response. 35 We found that the treatment with ORY-1001 decreased the expression of TGF-β1 mRNA in UUO kidneys compared to that in the vehicletreated kidneys (Figure S7A). In addition, targeting LSD1 with ORY-1001 or siRNA also decreased the expression of TGF-β1 mRNA in renal fibroblasts (Figure S7B,C).…”

“…The activation of renal fibroblasts, the main effector cells in fibrogenesis following kidney injury, mainly contribute to the increased synthesis of matrix components.TGF‐β1 has been reported to play a central role in mediating renal fibroblast activation and the deposition of excessive ECM in response to renal injury 34 . LSD1 inhibition has been reported to reduce the supernatant TGFβ1 secretion in Ang II‐induced cardiac myofibroblasts, implying the possible involvement of LSD1 in TGFβ‐related fibrotic response 35 . We found that the treatment with ORY‐1001 decreased the expression of TGF‐β1 mRNA in UUO kidneys compared to that in the vehicle‐treated kidneys (Figure S7A).…”

Fine-tuned KDM1A alternative splicing regulates human cardiomyogenesis through an enzymatic-independent mechanism

“…In addition, KDM1A −/− cardiac cells display improper upregulation of genes related to lipid metabolism. Relevantly, hyperlipidemia is associated with cardiac fibrosis ( Ma et al., 2013 ), and a recent study reported increased cardiac fibrosis in KDM1A −/− cardiac cells in vivo ( Huo et al., 2021 ). Therefore, we could speculate that KDM1A ablation promotes cardiac tissue fibrosis by the upregulation of cholesterol and lipid-related pathways.…”