Abstract 1536: Histone Demethylase LSD1 Modulates Angiotensin II Induced Interleukin-6 Expression in Human Aortic Smooth Muscle Cells
The dynamics of chromatin structure and the modifications of histones, which are coordinated by protein complexes containing multiple enzymatic activities, are key underlying mechanisms for eukaryotic gene regulation. Our discovery of LSD1, the first bona fide histone lysine demethylase, has revealed the reversible nature of histone methylation, therefore, bringing the 40-year-long debate on the reversibility of histone methylation to an end. However, little is known about the biological and physiological role of LSD1 demethylase. Here, we investigated the role of LSD1 in cardiovascular pathophysiology. Using chromatin immunoprecipetation (ChIP) assay and Real-time RT-PCR, we demonstrated that LSD1 complex is physically associated with the promoter region of interleukin-6 (IL-6) gene and regulates the expression of IL-6, a key cytokine in chronic inflammation and has been implicated in the progression of atherosclerosis. Furthermore, using a novel AAV-based siRNA delivery system, we were able to efficiently knockdown LSD1 expression in vascular smooth muscle cells (VSMC). We demonstrated that treating the cells with angiotensin II (10−6 M) in combination with the LSD1 siRNA enhanced the mRNA level of IL-6 by 95% (p < 0.01), suggesting that LSD1 plays an important role in regulating the response of VSMC to the pro-athrogenic stimuli. In summary, these findings indicate that LSD1 is directly involved in controlling a subset of inflammatory responsive genes in human VSMC and plays an important role in vascular pathophysiology. The data also suggest that LSD1 may have significant role in modulating VSMC response to pro-inflammatory effect of angiotensin II. Thus, it may provide novel strategies for prevention of atherosclerosis.