Changes in Zn homeostasis during long term culture of primary endothelial cells and effects of Zn on endothelial cell senescence

Abstract

Endothelial cell senescence and Zn nutritional status influence cardiovascular disease. The influence of Zn appears dichotomous, hence it is imperative to understand the relationship with cellular senescence to improve knowledge about the molecular and cellular basis of the disease. Here we aimed to determine: 1) the impact of chronic exposure to a moderately high dose of Zn on senescence of endothelial cells; 2) the changes in Zn homeostasis during the lifespan of primary cultured endothelial cells; and 3) the susceptibility of proliferating and senescent endothelial cells to cell death after short term exposure to increasing doses of Zn and of the Zn chelator TPEN. Chronic exposure to Zn accelerated senescence and untreated cells at later passages, where doubling time had increased, displayed relocation of labile Zn and altered expression of genes involved in the response to Zn toxicity, including SLC30A1, SLC39A6, SLC30A5, SLC30A10 and metallothioneins, indicating that senescent cells have altered zinc homeostasis. Most Zn-dependent genes that were expressed differently between early and late passages were correlated with changes in the expression of anti-apoptotic genes. Short-term treatment with a high dose of Zn leads to cell death, but only in the population of cells at both earlier and later passages that had already entered senescence. In contrast, Zn depletion led to death of cells at earlier but not later passages, which suggests that there are sub-populations of senescent cells that are resistant to Zn depletion. This resistant senescent cell population may accumulate under conditions of Zn deficiency and contribute to vascular pathology.

The Relationship between Serum Zinc Level and Heart Failure: A Meta-Analysis

“…Cellular senescence was discovered as strong driver of atherosclerosis and heart failure [ 39 , 40 ]. Recent observation performed on long-term culture of primary endothelial cells suggests that zinc deficiency may lead to accumulation of senescent cells and to vascular pathology as well as to heart failure [ 41 ]. Also, in HF patients, treatment with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) results in increased urinary zinc excretion and zinc deficiency [ 37 ].…”

Investigation of quercetin and hyperoside as senolytics in adult human endothelial cells

“…HUVECs are derived from the umbilical cord of newborn babies, and for a long time were the only model of primary human EC; however, these cells are not the best model of diseases associated with human arterial aging. HUVECs have been shown to differ substantially from primary endothelial cells derived from adult human vasculature [ 18 – 21 ]. In the current study, we investigated whether quercetin is a senolytic in adult EC, and evaluated whether Q3G would be a more selective senolytic.…”

“…Recent work reporting quercetin's potential as a senolytic used irradiation-induced senescent HUVECs, but HUVECs, which are derived from the umbilical vein of newborns, are far removed from aging adult human arterial vascular endothelial cells (EC). Not surprisingly, important differences have been found between adult EC and HUVEC [ 18 – 21 ]. Furthermore, quercetin’s low therapeutic/toxic ratio in the HUVEC study [ 14 ] raised the possibility that quercetin could significantly injure non-senescent cells.…”

Inducers of Senescence, Toxic Compounds, and Senolytics: The Multiple Faces of Nrf2-Activating Phytochemicals in Cancer Adjuvant Therapy

“…A relevant feature of some, but not all [ 33 ], senescent cells is their long-term survival and resistance to apoptosis [ 34 ], which likely contributes to their persistence and the respective deleterious consequences in aged tissues. A direct demonstration that senescent cells can drive age-related pathologies has been originally provided with the development of a transgenic mouse model, in which p16-expressing cells can be specifically eliminated upon drug treatment, with consequent prevention, delay, or attenuation of some age-related disorders [ 35 ].…”