View details for Web of Science ID 000460565900648
The heat shock response is an important cytoprotective mechanism for protein homeostasis and is an essential protective response to cellular stress and injury. Studies on changes in the heat shock response with aging have been mixed with regard to whether it is inhibited, and this, at least in part, reflects different tissues and different models. Cellular senescence is a key feature in aging, but work on the heat shock response in cultured senescent (SEN) cells has largely been limited to fibroblasts. Given the prevalence of oxidative injury in the aging cardiovascular system, we investigated whether SEN primary human coronary artery endothelial cells have a diminished heat shock response and impaired proteostasis. In addition, we tested whether this downregulation of heat shock response can be mitigated by 17?-estradiol (E2), which has a critical cardioprotective role in women, as we have previously reported that E2 improves the heat shock response in endothelial cells (Hamilton KL, Mbai FN, Gupta S, Knowlton AA. Arterioscler Thromb Vasc Biol 24: 1628-1633, 2004). We found that SEN endothelial cells, despite their unexpectedly increased proteasome activity, had a diminished heat shock response and had more protein aggregation than early passage cells. SEN cells had increased oxidative stress, which promoted protein aggregation. E2 treatment did not decrease protein aggregation or improve the heat shock response in either early passage or SEN cells. In summary, cellular senescence in adult human endothelial cells is accompanied by increased oxidative stress and a blunting of proteostasis, and E2 did not mitigate these changes. NEW & NOTEWORTHY Senescent human endothelial cells have a diminished heat shock response and increased protein aggregates. Senescent human endothelial cells have increased basal oxidative stress, which increases protein aggregates. Physiological level of 17?-estradiol did not improve proteostasis in endothelial cells.
View details for DOI 10.1152/ajpheart.00318.2018
View details for Web of Science ID 000457733800020
View details for PubMedID 30499713
View details for DOI 10.1371/journal.pone.0190374
Endothelial dysfunction, including upregulation of inflammatory adhesion molecules and impaired vasodilatation, is a key element in cardiovascular disease. Aging and estrogen withdrawal in women are associated with endothelial inflammation, vascular stiffness and increased cardiovascular disease. Epoxyecosatrienoic acids (EETs), the products of arachidonic acid metabolism mediated by cytochrome P450 (CYP) 2J, 2C and other isoforms, are regulated by soluble epoxide hydrolase (sEH)-catalyzed conversion into less active diols. We hypothesized that 11,12-EETs would reduce the endothelial dysfunction associated with aging and estrogen loss.When stabilized by an sEH inhibitor (seHi), 11,12-EET at a physiologically low dose (0.1nM) reduced cytokine-stimulated upregulation of adhesion molecules on human aorta endothelial cells (HAEC) and monocyte adhesion under shear flow through marked depolarization of the HAEC when combined with TNF?. Mechanistically, neither 11,12-EETs nor 17?-estradiol (E2) at physiologic concentrations prevented activation of NF?B by TNF?. E2 at physiological concentrations reduced sEH expression in HAEC, but did not alter CYP expression, and when combined with TNF? depolarized the cell. We also examined vascular dysfunction in adult and aged ovariectomized Norway brown rats (with and without E2 replacement) using an ex-vivo model to analyze endothelial function in an intact segment of artery. sEHi and 11,12-EET with or without E2 attenuated phenylephrine induced constriction and increased endothelial-dependent dilation of aortic rings from ovariectomized rats.Increasing 11,12-EETs through sEH inhibition effectively attenuates inflammation and may provide an effective strategy to preserve endothelial function and prevent atherosclerotic heart disease in postmenopausal women.
View details for DOI 10.1016/j.yjmcc.2016.03.019
View details for Web of Science ID 000376839000019
View details for PubMedID 27079253
View details for PubMedCentralID PMC4972711
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Recover, Restore and Re-open framework is a tool to guide communities as they reestablish operations during different stages of the COVID-19 pandemic.
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Latest information on COVID-19
Stanford Medicine is closely monitoring the outbreak of novel coronavirus (COVID-19). A new page is dedicated to the latest information and developments about COVID-19.
Racism and discrimination are direct affronts to Stanford Medicine?s values. Read our leaders? pledge on racial equity.
A leader in the biomedical revolution, Stanford Medicine has a long tradition of leadership in pioneering research, creative teaching protocols and effective clinical therapies.
An at-home COVID-19 test, designed by Stanford researchers to be easy to use and provide results within 30 minutes, will be the focus of a study funded by the Stanford Medicine Catalyst Program.
Our scientists have launched dozens of research projects as part of the global response to COVID-19. Some aim to prevent, diagnose and treat the disease; others aim to understand how it spreads and how people?s immune systems respond to it.
We are here for you and with your help, we will get through this together.
Recover, Restore and Re-open framework is a tool to guide communities as they reestablish operations during different stages of the COVID-19 pandemic.
A look at Stanford Medicine?s response to the new coronavirus, as well as outside perspectives on the pandemic.