Arterial alpha(2)-Na+ pump expression influences blood pressure: lessons from novel, genetically engineered smooth muscle-specific alpha(2) mice

作者：Chen Ling; Song Hong; Wang Youhua; Lee Jane C; Kotlikoff Michael I; Pritchard Tracy J; Paul Richard J; Zhang Jin; Blaustein Mordecai P^*

来源：American Journal of Physiology - Heart and Circulatory Physiology, 2015, 309(5): H958-H968.

DOI：10.1152/ajpheart.00430.2015

• Na+/Ca+ exchanger 1
• alpha(2)-Na+ pump
• angiotensin II
• salt
• sarco (endo)plasmic reticulum Ca2+-ATPase 2
• blood pressure

Arterial myocytes express alpha(1)-catalytic subunit isoform Na+ pumps (75-80% of total), which are ouabain resistant in rodents, and high ouabain affinity alpha(2)-Na+ pumps. Mice with globally reduced alpha(2)-pumps (but not alpha(1)-pumps), mice with mutant ouabain-resistant alpha(2)-pumps, and mice with a smooth muscle (SM)-specific alpha(2)-transgene (alpha(SM-Tg)(2)) that induces overexpression all have altered blood pressure (BP) phenotypes. We generated alpha(SM-DN)(2) mice with SM-specific alpha(2) (not alpha(1)) reduction (>50%) using nonfunctional dominant negative (DN) alpha(2). We compared alpha(SM-DN)(2) and alpha(SM-Tg)(2) mice to controls to determine how arterial SM alpha(2)-pumps affect vasoconstriction and BP. alpha(SM-DN)(2) 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 Ca2+ transporters, including Na+/Ca2+ exchanger 1 (NCX1) and sarcoplasmic reticulum and plasma membrane Ca2+ pumps [sarco(endo) plasmic reticulum Ca2+-ATPase 2 (SERCA2) and plasma membrane Ca2+-ATPase 1 (PMCA1)], were also reduced (>50%). alpha(SM-DN)(2) mouse isolated small arteries had reduced myogenic reactivity, perhaps because of reduced Ca2+ transporter expression. In contrast, alpha(2) SM-Tg mouse aortas overexpressed alpha(2) (alpha(2)-fold), NCX1, SERCA2, and PMCA1 (43). alpha(SM-Tg)(2) 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-alpha(2) engineered mice but was directly related in SM-NCX1 engineered mice. NCX1, which usually mediates arterial Ca2+ entry, and alpha(2)-Na+ pumps colocalize at plasma membrane-sarcoplasmic reticulum junctions and functionally couple via the local Na+ gradient to help regulate cell Ca2+. Altered Ca2+ transporter expression in SM-alpha(2) engineered mice apparently compensates to minimize Ca2+ overload (alpha(SM-DN)(2)) or depletion (alpha(SM-Tg)(2)) and attenuate BP changes. In contrast, Ca2+ transporter upregulation, observed in many rodent hypertension models, should enhance Ca2+ entry and signaling and contribute significantly to BP elevation.

• 出版日期2015-9-1