Arterial α₂-Na⁺pump expression influences blood pressure: lessons from novel, genetically engineered smooth muscle-specific α₂mice

Abstract

MP. Arterial ␣ 2-Na ϩ pump expression influences blood pressure: lessons from novel, genetically engineered smooth muscle-specific ␣ 2 mice. Am J Physiol Heart Circ Physiol 309: H958 -H968, 2015. First published July 25, 2015; doi:10.1152/ajpheart.00430.2015.-Arterial myocytes express ␣ 1-catalytic subunit isoform Na ϩ pumps (75-80% of total), which are ouabain resistant in rodents, and high ouabain affinity ␣ 2-Na ϩ pumps. Mice with globally reduced ␣ 2-pumps (but not ␣1-pumps), mice with mutant ouabain-resistant ␣ 2-pumps, and mice with a smooth muscle (SM)-specific ␣ 2-transgene (␣2 SM-Tg ) that induces overexpression all have altered blood pressure (BP) phenotypes. We generated ␣ 2 SM-DN mice with SM-specific ␣2 (not ␣1) reduction (Ͼ50%) using nonfunctional dominant negative (DN) ␣ 2. We compared ␣2 SM-DN and ␣ 2 SM-Tg mice to controls to determine how arterial SM ␣2-pumps affect vasoconstriction and BP. ␣ 2 SM-DN mice had elevated basal mean BP (mean BP by telemetry: 117 Ϯ 4 vs. 106 Ϯ 1 mmHg, n ϭ 7/7, P Ͻ 0.01) and enhanced BP responses to chronic ANG II infusion (240 ng·kg Ϫ1 ·min Ϫ1 ) and high (6%) NaCl. Several arterial Ca 2ϩ transporters, including Na ϩ /Ca 2ϩ exchanger 1 (NCX1) and sarcoplasmic reticulum and plasma membrane Ca 2ϩ pumps [sarco(endo)plasmic reticulum Ca 2ϩ -ATPase 2 (SERCA2) and plasma membrane Ca 2ϩ -ATPase 1 (PMCA1)], were also reduced (Ͼ50%). ␣2SM-DN mouse isolated small arteries had reduced myogenic reactivity, perhaps because of reduced Ca 2ϩ transporter expression. In contrast, ␣2 SM-Tg mouse aortas overexpressed ␣2 (Ͼ2-fold), NCX1, SERCA2, and PMCA1 (43). ␣2 SM-Tg mice had reduced basal mean BP (104 Ϯ 1 vs. 109 Ϯ 2 mmHg, n ϭ 15/9, P Ͻ 0.02) and attenuated BP responses to chronic ANG II (300 -400 ng·kg Ϫ1 ·min Ϫ1 ) with or without 2% NaCl but normal myogenic reactivity. NCX1 expression was inversely related to basal BP in SM-␣2 engineered mice but was directly related in SM-NCX1 engineered mice. NCX1, which usually mediates arterial Ca 2ϩ entry, and ␣2-Na ϩ pumps colocalize at plasma membrane-sarcoplasmic reticulum junctions and functionally couple via the local Na

Pivotal role of α2 Na+ pumps and their high affinity ouabain binding site in cardiovascular health and disease

“…Also, ∼65% knockdown of α2 decreased NCX1 by ∼65%, but did not affect α1 expression in arteries (Chen et al . b ).…”

“…; Chen et al . b ). Conversely, mice with SM‐specific α2 overexpression (α2 SM‐Tg ) and excess α2 EO binding sites, have low basal BP (Pritchard et al .…”

“…; Chen et al . b ). Conversely, transgenic overexpression of SM‐α2 lowers BP and causes a secondary increase in NCX1 and SERCA2 expression, probably to compensate, partially, for the BP reduction which may be due to a fall in [Ca 2+ ] CYT (Pritchard et al .…”

“…; Chen et al . b ). In contrast, primary SM‐NCX1 overexpression increases [Ca 2+ ] CYT and elevates BP (Iwamoto et al .…”

“…), or smooth muscle (SM)‐specific dominant negative (DN) knockdown, α2 SM‐DN (Chen et al . b ), also have elevated BP. (Global α2 −/− is embryonic lethal; James et al .…”