Figure 5

The intrinsically coupled dyshomeostasis of Ca²⁺ and Zn²⁺ found in aldosterone/salt treatment (ALDOST). Increased excretory losses of these divalent cations lead to hypocalcemia and hypozincemia. Secondary hyperparathyroidism with persistent elevations in circulating parathyroid hormone (PTH) follows and are accompanied by uncontrolled Ca²⁺ entry via L-type Ca²⁺ channels (LTCC) to saturate intracellular binding and storage sites, and ultimately to [Ca²⁺]_i overloading and excessive [Ca²⁺]_m within the mitochondria. An induction of oxidative stress and generation of reactive oxygen species (ROS) ensues arising from the mitochondria. The rise in [Zn²⁺]_i and [Zn²⁺]_m involves increased Zn²⁺ entry via LTCC to a minor extent, whereas the majority of [Zn²⁺]_i is regulated by membrane-bound Zn transporters, including Zip1 and ZnT-1, and its binding to metallothionein (Zn/MT). ROS serve as signals that initiate an activation of molecular transducers. These include: stress-response kinases, MAPKs, and their activation of redox-sensitive nuclear transcription factor (NF)-κB and a proinflammatory gene cascade it induces, including adhesion molecules (ICAM-1), chemokines (MCP-1) and cytokines tumor necrosis factor-α (TNF-α) and tumor growth factor-β (TGF-β); and the activation of inducible or endothelial nitric oxide synthases (iNOS and eNOS), where nitric oxide (NO) generation releases Zn²⁺ from the Zn/MT complex. Increased [Zn²⁺]_i serves to activate its sensor, metal-response element transcription factor (MTF)-1, and the antioxidant genes it induces. These include MT-1, Cu/Zn-SOD and glutathione (GSH) synthase. Increased [Ca²⁺]_i and [Ca²⁺]_m are pro-oxidants, which in toxic amounts threaten the fate of cardiomyocytes, whereas increments in [Zn²⁺]_i and [Zn²⁺]_m are antioxidants. Reprinted from Kamalov G, et al. J Cardiovasc Pharmacol 2009; 53: 414–423, with permission.