Regulation of angiotensin II actions by enhancers and super-enhancers in vascular smooth muscle cells

Sadhan Das, Parijat Senapati, Zhuo Chen, Marpadga A. Reddy, Rituparna Ganguly, Linda Lanting, Varun Mandi, Anita Bansal, Amy Leung, Selena Zhang, Ye Jia, Xiwei Wu, Dustin E. Schones and Rama Natarajan ()
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Sadhan Das: Diabetes Metabolism Research Institute, Beckman Research Institute of City of Hope
Parijat Senapati: Diabetes Metabolism Research Institute, Beckman Research Institute of City of Hope
Zhuo Chen: Diabetes Metabolism Research Institute, Beckman Research Institute of City of Hope
Marpadga A. Reddy: Diabetes Metabolism Research Institute, Beckman Research Institute of City of Hope
Rituparna Ganguly: Diabetes Metabolism Research Institute, Beckman Research Institute of City of Hope
Linda Lanting: Diabetes Metabolism Research Institute, Beckman Research Institute of City of Hope
Varun Mandi: Diabetes Metabolism Research Institute, Beckman Research Institute of City of Hope
Anita Bansal: Diabetes Metabolism Research Institute, Beckman Research Institute of City of Hope
Amy Leung: Diabetes Metabolism Research Institute, Beckman Research Institute of City of Hope
Selena Zhang: Diabetes Metabolism Research Institute, Beckman Research Institute of City of Hope
Ye Jia: Diabetes Metabolism Research Institute, Beckman Research Institute of City of Hope
Xiwei Wu: Beckman Research Institute of City of Hope
Dustin E. Schones: Diabetes Metabolism Research Institute, Beckman Research Institute of City of Hope
Rama Natarajan: Diabetes Metabolism Research Institute, Beckman Research Institute of City of Hope

Nature Communications, 2017, vol. 8, issue 1, 1-19

Abstract: Abstract Angiotensin II (AngII) promotes hypertension and atherosclerosis by activating growth-promoting and pro-inflammatory gene expression in vascular smooth muscle cells (VSMCs). Enhancers and super-enhancers (SEs) play critical roles in driving disease-associated gene expression. However, enhancers/SEs mediating VSMC dysfunction remain uncharacterized. Here, we show that AngII alters vascular enhancer and SE repertoires in cultured VSMCs in vitro, ex vivo, and in AngII-infused mice aortas in vivo. AngII-induced enhancers/SEs are enriched in binding sites for signal-dependent transcription factors and dependent on key signaling kinases. Moreover, CRISPR-Cas9-mediated deletion of candidate enhancers/SEs, targeting SEs with the bromodomain and extra-terminal domain inhibitor JQ1, or knockdown of overlapping long noncoding RNAs (lncRNAs) blocks AngII-induced genes associated with growth-factor signaling and atherosclerosis. Furthermore, JQ1 ameliorates AngII-induced hypertension, medial hypertrophy and inflammation in vivo in mice. These results demonstrate AngII-induced signals integrate enhancers/SEs and lncRNAs to increase expression of genes involved in VSMC dysfunction, and could uncover novel therapies.

Date: 2017
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DOI: 10.1038/s41467-017-01629-7

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