Cytoglobin is a widely expressed heme protein that binds oxygen, carbon monoxide and nitric oxide. Recent examination of cytoglobin in the vasculature indicates that it contributes to nitric oxide availability, which is central to normal blood vessel function through regulation of smooth muscle cell tone and physiological response. Given the potential implications of cytoglobin in vascular function, we examined how cytoglobin might be uniquely regulated in vascular smooth muscle cells. Our data demonstrate that endothelial cells can increase the expression of cytoglobin in vascular smooth muscle cells, and the induction of cytoglobin is cell contact-dependent. We show that Notch signaling is necessary for endothelial cell-induced cytoglobin expression and Notch2 and Notch3 are sufficient to drive its expression in aortic smooth muscle cells. We further reveal that in cytoglobin-depleted smooth muscle cells there is increased cellular nitric oxide. These data demonstrate that, in addition to being the main producer of vascular nitric oxide, endothelial cells facilitate the ability of smooth muscle cells to metabolize nitric oxide through upregulation of cytoglobin. Our results reveal a novel mechanism by which Notch signaling contributes to vascular function through regulation of a gene that controls nitric oxide levels.
Cardiac fibrosis is associated with many types of cardiovascular diseases and is characterized by the deposition of excess extracellular matrix by the cardiac fibroblasts. Previous studies demonstrated that microRNA miR‐145 acts as an inhibitor of fibrosis by targeting the profibrotic TGFβ pathway. Our preliminary data suggest that within the TGFβ pathway, miR‐145 specifically targets the p38 mitogen‐activated protein (MAP) kinase signaling, which is known to activate cardiac fibroblasts and drive the fibrotic response. Therefore, I hypothesize that miR‐145 targets the p38 MAP kinase pathway to regulate cardiac fibroblast activation and suppress fibrosis. Human cardiac fibroblasts (hCFs) were transfected with a miR‐145 mimic or a control mimic and TGFβ, a fibrotic agonist, was added to activate fibroblasts. Cells were processed for RNA and quantitative‐PCR was used to measure relative expression of genes within the p38 MAP kinase pathway. My findings show that MAP2K3 and MAP4K4 expression are inhibited by miR‐145 in activated hCFs. Further, TGFβ 3 and RGS2, both negative regulators of fibrosis, were induced in miR‐145 treated cells. These data indicate that miR‐145 modulates components of the p38 MAP kinase signaling pathway, which may contribute to its ability to regulate cardiac fibrosis. Ongoing studies will examine if overexpression of miR‐145 in a mouse model will affect the expression of these p38 MAP kinase mediators and contribute to a reduction in cardiac fibrosis.Support or Funding InformationThis project was supported by the American Physiological Society‐Undergraduate Research Excellency Fellowship, the American Heart Association Summer Undergraduate Research Fellowship, and the National Institute of Health grant R01‐HL‐135657 (to B. Lilly).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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