title: Pivotal role of α2 Na+pumps and their high affinity ouabain binding site in cardiovascular health and disease.
abstract: Reduced smooth muscle (SM)-specific α2 Na+pump expression elevates basal blood pressure (BP) and increases BP sensitivity to angiotensin II (Ang II) and dietary NaCl, whilst SM-α2 overexpression lowers basal BP and decreases Ang II/salt sensitivity. Prolonged ouabain infusion induces hypertension in rodents, and ouabain-resistant mutation of the α2 ouabain binding site (α2R/Rmice) confers resistance to several forms of hypertension. Pressure overload-induced heart hypertrophy and failure are attenuated in cardio-specific α2 knockout, cardio-specific α2 overexpression and α2R/Rmice. We propose a unifying hypothesis that reconciles these apparently disparate findings: brain mechanisms, activated by Ang II and high NaCl, regulate sympathetic drive and a novel neurohumoral pathway mediated by both brain and circulating endogenous ouabain (EO). Circulating EO modulates ouabain-sensitive α2 Na+pump activity and Ca2+transporter expression and, via Na+/Ca2+exchange, Ca2+homeostasis. This regulates sensitivity to sympathetic activity, Ca2+signalling and arterial and cardiac contraction.
authors.affiliation: Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. mblaustein@som.umaryland.edu.|Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. mblaustein@som.umaryland.edu.
authors.forename: Mordecai P
authors.initials: MP
authors.lastname: Blaustein
authors.affiliation: Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.|Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Hamlyn
authors.affiliation: Hypertension Unit, University of Ottawa Heart Institute, Ottawa, ON, Canada, K1Y 4W7.
authors.forename: Frans H H
authors.initials: FH
authors.lastname: Leenen
authors.affiliation: Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH, 45267-0524, USA.
authors.forename: Jerry B
authors.initials: JB
authors.lastname: Lingrel
authors.affiliation: Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
authors.forename: W Gil
authors.initials: WG
authors.lastname: Wier
authors.affiliation: Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000809:Angiotensins / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002316:Cardiotonic Agents / Q000494:pharmacology; D002319:Cardiovascular System / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D010042:Ouabain / Q000494:pharmacology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D013564:Sympathetic Nervous System / Q000378:metabolism / Q000502:physiology
chemical_list: D000809:Angiotensins; D002316:Cardiotonic Agents; D010042:Ouabain; D000254:Sodium-Potassium-Exchanging ATPase
keywords: artery; cardiac hypertrophy; heart failure; hypertension