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microRNA‐204, SIRTUIN1, and Caveolin‐1 regulate vascular endoplasmic reticulum stress and endothelium‐dependent vasorelaxation
Author(s) -
Kassan Modar,
Vikram Ajit,
Li Qiuxia,
Kim YoungRae,
Kumar Santosh,
Jacobs Julia,
Irani kaikobad
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.727.1
Subject(s) - tunicamycin , unfolded protein response , endoplasmic reticulum , endothelial dysfunction , endothelium , vascular endothelial growth factor b , microbiology and biotechnology , endothelial stem cell , downregulation and upregulation , caveolin 1 , biology , endocrinology , chemistry , vascular endothelial growth factor a , medicine , cancer research , vascular endothelial growth factor , biochemistry , vegf receptors , gene , in vitro
Background Endoplasmic reticulum ( ER) stress leads to vascular endothelial dysfunction in disease states such as obesity, diabetes and hypertension. The role of microRNAs in vascular ER stress is not fully understood. Here we examined the role of vascular microRNA‐204 (miR‐204) in inducing endothelial ER stress and dysfunction by governing the expression of the SIRTUIN1 (SIRT1) lysine deacetylase and the Caveolin‐1 (Cav1). Methods & results miR‐204 mimic decreased expression of SIRT1 and Cav1, and promoted ER stress in endothelial cells. Tunicamycin induced endothelial ER stress was also mediated by miR‐204. Moreover, knockdown of SIRT1 induced ER stress and reduced Cav1 in endothelial cells, both of which were rescued by a miR‐204 antagomir. Tunicamycin‐induced ER stress upregulated miR‐204, and downregulated SIRT1 and Cav1, in endothelial cells. Similarly and in endothelium of aortas and mesenteric arteries of mice. Antagonism of miR‐204, or SIRT1 overexpression, rescued endothelial cells from tunicamycin‐induced ER stress. Similarly, antagonism of miR‐204 in vivo with anti‐miR‐204 mitigated tunicamycin‐induced vascular ER stress, decline in vascular SIRT1 and Cav1, and impairment of endothelium‐dependent vasorelaxation. Moreover, tunicamycin‐induced vascular ER stress and endothelial dysfunction were exacerbated in mice with conditional deletion of endothelial SIRT1. Additionally, overexpressing Cav1 ex‐vivo, with adenovirus, in tunicamycin‐induced vascular ER stress or in mice with conditional deletion of endothelial SIRT1, reduced ER stress markers and miR‐204 in endothelial cells and was associated with an improvement in vascular endothelial dependent relaxation. Finally, Vascular miR‐204 was upregulated with high‐fat diet feeding, anti‐miR‐204 prevented vascular ER stress stimulated by high‐fat diet feeding. Conclusions These findings show an important role for miR‐204 as a mediator of vascular ER stress, and ER stress‐induced endothelial dysfunction, via downregulation of endothelial SIRT1 and cav1. Support or Funding Information T32‐ Institutional Training Grant (HL007121)