Journal article
Mechanistic Target of Rapamycin Complex 1 Signaling Modulates Vascular Endothelial Function Through Reactive Oxygen Species
Journal of the American Heart Association, Vol.8(9), pp.e010662-e010662
05/07/2019
DOI: 10.1161/JAHA.118.010662
PMCID: PMC6512105
PMID: 31020916
Abstract
Background The mechanistic target of rapamycin complex 1 ( mTORC 1) is an important intracellular energy sensor that regulates gene expression and protein synthesis through its downstream signaling components, the S6-kinase and the ribosomal S6 protein. Recently, signaling arising from mTORC 1 has been implicated in regulation of the cardiovascular system with implications for disease. Here, we examined the contribution of mTORC 1 signaling to the regulation of vascular function. Methods and Results Activation of mTORC 1 pathway in aortic rings with leucine or an adenoviral vector expressing a constitutively active S6-kinase reduces endothelial-dependent vasorelaxation in an mTORC 1-dependent manner without affecting smooth muscle relaxation responses. Moreover, activation of mTORC 1 signaling in endothelial cells increases reactive oxygen species ( ROS ) generation and ROS gene expression resulting in a pro-oxidant gene environment. Blockade of ROS signaling with Tempol restores endothelial function in vascular rings with increased mTORC 1 activity indicating a crucial interaction between mTORC 1 and ROS signaling. We then tested the role of nuclear factor-κB transcriptional complex in connecting mTORC 1 and ROS signaling in endothelial cells. Blockade of inhibitor of nuclear factor κ-B kinase subunit β activity with BMS -345541 prevented the increased ROS generation associated with increased mTORC 1 activity in endothelial cells but did not improve vascular endothelial function in aortic rings with increased mTORC 1 and ROS signaling. Conclusions These results implicate mTORC 1 as a critical molecular signaling hub in the vascular endothelium in mediating vascular endothelial function through modulation of ROS signaling.
Details
- Title: Subtitle
- Mechanistic Target of Rapamycin Complex 1 Signaling Modulates Vascular Endothelial Function Through Reactive Oxygen Species
- Creators
- John J Reho - 1 Department of Pharmacology University of Iowa Carver College of Medicine Iowa City IADeng-Fu Guo - 1 Department of Pharmacology University of Iowa Carver College of Medicine Iowa City IAKamal Rahmouni - 3 Fraternal Order of Eagles Diabetes Research Center University of Iowa Iowa City IA
- Resource Type
- Journal article
- Publication Details
- Journal of the American Heart Association, Vol.8(9), pp.e010662-e010662
- Publisher
- England
- DOI
- 10.1161/JAHA.118.010662
- PMID
- 31020916
- PMCID
- PMC6512105
- ISSN
- 2047-9980
- eISSN
- 2047-9980
- Grant note
- P01 HL084207 / NHLBI NIH HHS I01 BX004249 / BLRD VA
- Language
- English
- Date published
- 05/07/2019
- Academic Unit
- Iowa Neuroscience Institute; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Internal Medicine
- Record Identifier
- 9984070683802771
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