Angiotensin II Requires Zinc and Downregulation of the Zinc Transporters ZnT3 and ZnT10 to Induce Senescence of Vascular Smooth Muscle Cells

Abstract

Senescence, a hallmark of mammalian aging, is associated with the onset and progression of cardiovascular disease. Angiotensin II (Ang II) signaling and zinc homeostasis dysfunction are increased with age and are linked to cardiovascular disease, but the relationship among these processes has not been investigated. We used a model of cellular senescence induced by Ang II in vascular smooth muscle cells (VSMCs) to explore the role of zinc in vascular dysfunction. We found that Ang II-induced senescence is a zinc-dependent pathway mediated by the downregulation of the zinc transporters ZnT3 and ZnT10, which work to reduce cytosolic zinc. Zinc mimics Ang II by increasing reactive oxygen species (ROS), activating NADPH oxidase activity and Akt, and by downregulating ZnT3 and ZnT10 and inducing senescence. Zinc increases Ang II-induced senescence, while the zinc chelator TPEN, as well as overexpression of ZnT3 or ZnT10, decreases ROS and prevents senescence. Using HEK293 cells, we found that ZnT10 localizes in recycling endosomes and transports zinc into vesicles to prevent zinc toxicity. Zinc and ZnT3/ZnT10 downregulation induces senescence by decreasing the expression of catalase. Consistently, ZnT3 and ZnT10 downregulation by siRNA increases ROS while downregulation of catalase by siRNA induces senescence. Zinc, siZnT3 and siZnT10 downregulate catalase by a post-transcriptional mechanism mediated by decreased phosphorylation of ERK1/2. These data demonstrate that zinc homeostasis dysfunction by decreased expression of ZnT3 or ZnT10 promotes senescence and that Ang II-induced senescence is a zinc and ROS-dependent process. Our studies suggest that zinc might also affect other ROS-dependent processes induced by Ang II, such as hypertrophy and migration of smooth muscle cells.

Direct Comparison of Manganese Detoxification/Efflux Proteins and Molecular Characterization of ZnT10 Protein as a Manganese Transporter

“…ZnT10 plays a role in zinc metabolism, locating the early/ recycling endosomes or the Golgi apparatus (26,27,65). However, we have no data to show that hZnT10 is involved in the detoxification of high zinc concentrations.…”

“…ZnT10 is localized to the plasma membrane and is functional in manganese metabolism by effluxing cytosolic manganese (24,25). ZnT10 is also involved in zinc homeostasis in subcellular localization (26,27). The finding that loss-of-function mutations of ATP13A2 and ZnT10 genes results in the development of parkinsonism accelerates the necessity to clarify manganese detoxification/efflux mechanisms in cells.…”

The Physiological, Biochemical, and Molecular Roles of Zinc Transporters in Zinc Homeostasis and Metabolism

“…Expression of ZnT10 is downregulated by IL-6 (108) and is suggested to be under the control of ZTRE, as in ZnT5 (63). The downregulation of ZnT10 along with ZnT3 by angiotensin II may be associated with cellular senescence in vascular smooth muscle cells (312). Homozygous mutations of the ZnT10 gene cause Parkinsonism and dystonia with hypermanganesemia, polycythemia, and hepatic cirrhosis (OMIM 613280) (341,417).…”

Zinc and the aging brain

“…Inadequate zinc intake certainly contributes to deficiency in many elderly patients (Singh et al 1998;Pepersack et al 2001) but effects of chronic inflammation and age-related decline in zinc transport mechanisms may also contribute to a functional zinc deficiency (Turnlund et al 1986;Wong et al 2012). For example, senescence of rat vascular smooth muscle cells involves decreased ZnT expression (Patrushev et al 2012) and an age-related decline in plasma zinc was associated with increased methylation of the ZIP6 promoter and an exaggerated inflammatory response in mice (Wong et al 2012). Furthermore, zinc supplementation restored plasma zinc levels leading to a reduction in markers of inflammation and oxidative stress in elderly subjects (Bao et al 2010).…”