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

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

Therapeutic approach of children with endocrine diseases in otorhinolaryngoiatric surgery

Almost all endocrine disorders may cause adverse complications or a difficult postoperative course if they are not recognized or adequately managed. Diabetes is the most commonly encountered endocrinopathy and there is increasing evidence that maintenance of normal blood glucose in the perioperative period is necessary to reduce adverse events. The perioperative management of diabetes should be based on the type of diabetes, the medications taken and degree of diabetes control. Thyrotoxicosis is a potentially severe condition that requires medical intervention before surgery. The preparation of a patient with hyperthyroidism depends on the time available before surgery and on the severity of the thyrotoxicosis. Generally, treatment involves a combination of medications that influence the synthesis, secretion and peripheral actions of thyroid hormones. Patients with mild hypothyroidism can undergo elective or emergency surgery without specific perioperative preparation. In case of adrenal insufficiency, supplementation of glucocorticoids (and possibly mineralocorticoids) should be adequately given and individualized on the basis of size and the type of surgical procedure to be performed. Finally, the management of children with diabetes insipidus, before or after a surgical procedure, or with the syndrome of inappropriate secretion of ADH is complicated and may cause severe electrolytic imbalances as well as problems of over- or under-hydration which can be difficult to treat. \ua9 Copyright 2006, CIC Edizioni Internazionali, Roma