title: Arterial α2-Na+ pump expression influences blood pressure: lessons from novel, genetically engineered smooth muscle-specific α2 mice.
abstract: Arterial myocytes express α1-catalytic subunit isoform Na(+) pumps (75-80% of total), which are ouabain resistant in rodents, and high ouabain affinity α2-Na(+) pumps. Mice with globally reduced α2-pumps (but not α1-pumps), mice with mutant ouabain-resistant α2-pumps, and mice with a smooth muscle (SM)-specific α2-transgene (α2 (SM-Tg)) that induces overexpression all have altered blood pressure (BP) phenotypes. We generated α2 (SM-DN) mice with SM-specific α2 (not α1) reduction (>50%) using nonfunctional dominant negative (DN) α2. We compared α2 (SM-DN) and α2 (SM-Tg) mice to controls to determine how arterial SM α2-pumps affect vasoconstriction and BP. α2 (SM-DN) mice had elevated basal mean BP (mean BP by telemetry: 117 ± 4 vs. 106 ± 1 mmHg, n = 7/7, P < 0.01) and enhanced BP responses to chronic ANG II infusion (240 ng·kg(-1)·min(-1)) and high (6%) NaCl. Several arterial Ca(2+) transporters, including Na(+)/Ca(2+) exchanger 1 (NCX1) and sarcoplasmic reticulum and plasma membrane Ca(2+) pumps [sarco(endo)plasmic reticulum Ca(2+)-ATPase 2 (SERCA2) and plasma membrane Ca(2+)-ATPase 1 (PMCA1)], were also reduced (>50%). α2 (SM-DN) mouse isolated small arteries had reduced myogenic reactivity, perhaps because of reduced Ca(2+) transporter expression. In contrast, α2 (SM-Tg) mouse aortas overexpressed α2 (>2-fold), NCX1, SERCA2, and PMCA1 (43). α2 (SM-Tg) mice had reduced basal mean BP (104 ± 1 vs. 109 ± 2 mmHg, n = 15/9, P < 0.02) and attenuated BP responses to chronic ANG II (300-400 ng·kg(-1)·min(-1)) with or without 2% NaCl but normal myogenic reactivity. NCX1 expression was inversely related to basal BP in SM-α2 engineered mice but was directly related in SM-NCX1 engineered mice. NCX1, which usually mediates arterial Ca(2+) entry, and α2-Na(+) pumps colocalize at plasma membrane-sarcoplasmic reticulum junctions and functionally couple via the local Na(+) gradient to help regulate cell Ca(2+). Altered Ca(2+) transporter expression in SM-α2 engineered mice apparently compensates to minimize Ca(2+) overload (α2 (SM-DN)) or depletion (α2 (SM-Tg)) and attenuate BP changes. In contrast, Ca(2+) transporter upregulation, observed in many rodent hypertension models, should enhance Ca(2+) entry and signaling and contribute significantly to BP elevation.
authors.affiliation: Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland; Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland;
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland;
authors.forename: Hong
authors.initials: H
authors.lastname: Song
authors.affiliation: Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland;
authors.forename: Youhua
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York;
authors.forename: Jane C
authors.initials: JC
authors.lastname: Lee
authors.affiliation: Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York;
authors.forename: Michael I
authors.initials: MI
authors.lastname: Kotlikoff
authors.affiliation: College of Nursing, College of Medicine, University of Cincinnati, Cincinnati, Ohio; and.
authors.forename: Tracy J
authors.initials: TJ
authors.lastname: Pritchard
authors.affiliation: Department of Molecular and Cell Physiology, College of Medicine, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Paul
authors.affiliation: Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland;
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland; Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland; mblaustein@som.umaryland.edu.
authors.forename: Mordecai P
authors.initials: MP
authors.lastname: Blaustein
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001158:Arteries / Q000378:metabolism* / Q000502:physiology; D001794:Blood Pressure; D051379:Mice; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000235:genetics / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics / Q000378:metabolism*
chemical_list: C499849:NCX1 protein, mouse; D021122:Protein Subunits; D019831:Sodium-Calcium Exchanger; D000804:Angiotensin II; D053499:Plasma Membrane Calcium-Transporting ATPases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506947:Atp2a2 protein, mouse; C506954:Atp2b1 protein, mouse; D000254:Sodium-Potassium-Exchanging ATPase
keywords: Na+/Ca+ exchanger 1; angiotensin II; blood pressure; salt; sarco(endo)plasmic reticulum Ca2+-ATPase 2; α2-Na+ pump