Affiliations: Departments of Clinical and Diagnostic Sciences,
University of Alabama at Birmingham, Birmingham, AL, USA | Departments of Biochemistry and Molecular Genetics,
University of Alabama at Birmingham, Birmingham, AL, USA
Note: [] Corresponding author: Menjor Tino Unlap, Departments of Clinical
and Diagnostic Sciences and Biochemistry and Molecular Genetics, 476 SHPB
University of Alabama at Birmingham, Birmingham, AL 35294, USA. Tel.: +1 205
934 7382; Fax: +1 205 975 730; E-mail: [email protected]
Abstract: Oxidative stress-induced hypertension involves a number of membrane
transport proteins that play a critical role in maintaining the cytosolic
homeostasis of Na^+ and Ca^{2+}. These
transport proteins include
Na^+/K^+-ATPase, the
Na^+/H^+ exchanger, Na channels, and the
Na^+/Ca^{2+} exchanger. The exact link
between these membrane transporters is not exactly known but appears to involve
their location in microdomains called PLasmERosomes, oxidative stress and
circulating ouabain levels. Oxidative stress stimulates the generation of
ouabain from the adrenal glands which elevates circulating endogenous ouabain
levels. At concentrations above 1nM, ouabain inhibits the activity of the
Na^+/K^+-ATPase. At 1nM or lower
concentrations, the Na^+/K^+-ATPase acts
as a transducer which induces a cascade of events that begins with
phosphorylation of the epidermal growth factor receptor (EGFR) by Src and
activation of Ras, Raf, mitogen activated protein kinase kinase (MEK), mitogen
activated protein kinase (MAPK), extracellular signal-regulated kinase1/2
(ERK1/2), and p90 ribosomal S6 kinase (p90RSK). p90RSK activates the
Na^+/H^+ exchanger through
phosphorylation. Ouabain-mediated inhibition and activation of the
Na^+/K^+-ATPase and
Na^+/H^+ exchanger, respectively, leads
to elevation of Na^+ in the PLasmERosome which stimulates
the Na^+/Ca^{2+} exchanger to extrude
Na^+ in exchange for Ca^{2+}. This
elevates Ca^{2+} in the PLasmERosome which stimulates
junctional ER to release Ca^{2+}. Ca^{2+}
influx through the Na^+/Ca^{2+} exchanger
and release from junctional ER leads to Ca^{2+} overload
which can lead to a number of pathologies including increased vascular tone and
hypertension.
