Transgenic mice expressing Na+-K+-ATPase in smooth muscle decreases blood pressure

Abstract

The Na+-K+-ATPase (NKA) is a transmembrane protein that sets and maintains the electrochemical gradient by extruding three Na+ in exchange for two K+. An important physiological role proposed for vascular smooth muscle NKA is the regulation of blood pressure via modulation of vascular smooth muscle contractility ( 5 ). To investigate the relations between the level of NKA in smooth muscle and blood pressure, we developed mice carrying a transgene for either the NKA α1- or α2-isoform (α1sm+ or α2sm+ mice) driven by the smooth muscle-specific α-actin promoter SMP8. Interestingly, both α-isoforms, the one contained in the transgene and the one not contained, were increased to a similar degree at both protein and mRNA levels. The total α-isoform protein was increased from 1.5-fold (α1sm+ mice) to 7-fold (α2sm+ mice). The increase in total NKA α-isoform protein was accompanied by a 2.5-fold increase in NKA activity in α2sm+ gastric antrum. Immunocytochemistry of the α1- and α2-isoforms in α2sm+ aortic smooth muscle cells indicated that α-isoform distributions were similar to those shown in wild-type cells. α2sm+ Mice (high expression) were hypotensive (109.9 ± 1.6 vs. 121.3 ± 1.4 mmHg; n = 13 and 11, respectively), whereas α1sm+ mice (low expression) were normotensive (122.7 ± 2.5 vs. 117.4 ± 2.3; n = 11 or 12). α2sm+ Aorta, but not α1sm+ aorta, relaxed faster from a KCl-induced contraction than wild-type aorta. Our results show that smooth muscle displays unique coordinate expression of the α-isoforms. Increasing smooth muscle NKA decreases blood pressure and is dependent on the degree of increased α-isoform expression.