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Expression and Function of the Na +-K +ATPase α-Isoforms in Smooth Muscle: Evidence from Transgenic Mice

PRITCHARD, TRACY J.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1186672962

Abstract Details

2007, PhD, University of Cincinnati, Medicine : Molecular and Cellular Physiology.
An important physiological role proposed for vascular smooth muscle Na +-K +ATPase (NKA) is the regulation of blood pressure via modulation of vascular smooth muscle contractility. To investigate the effects of a gain of function of NKA specifically in smooth muscle, we developed mice carrying a transgene for either the NKA α1- or α2-isoform (α1 sm+or α2 sm+mice) ligated to the smooth muscle specific α-actin promoter, SMP8. The α1 sm+mice displayed a 1.5-fold increase in the α1-isoform, while the α2 sm+mice had a 2-6-fold increase in the α2-isoform. Interestingly, the α-isoform not contained in the transgene was also increased to a similar degree for both transgenic lines, which was evident at the mRNA level as well. The increase in total NKA α-isoform protein was accompanied by a ~1.25- to 2.5-fold increase in NKA activity in gastric antrum from α1 sm+and α2 sm+mice respectively. The α2 sm+mice (high expression) were hypotensive relative to WT mice (109.9 ± 1.6 mmHg, n=13 vs. 121.3 ± 1.4 mmHg, n=11), whereas α1 sm+mice (low expression) were normotensive (122.7 ± 2.5 mmHg, n=11 vs. 117.4 ± 2.3 mmHg, n=12). Our results show that smooth muscle displays unique coordinate expression of NKA α-isoforms. Additionally, increasing smooth muscle NKA decreases blood pressure, which appears to be dependent on the degree of α-isoform expression. To elucidate mechanisms underlying the decrease in blood pressure, we examined pathways of intracellular Ca 2+regulation. Relaxation half-times from a KCl-induced contraction were significantly decreased in α2 sm+aorta but not α1 sm+aorta relative to paired WT aorta. Proteins involved in Ca 2+clearance (Na +-Ca 2+exchanger-NCX and plasma membrane Ca 2+ATPase-PMCA) and sequestration (sarcoplasmic reticulum Ca 2+ATPase-SERCA) were increased up to 5-fold in smooth muscle from α2 sm+mice, supporting enhanced Ca 2+clearance. Resting intracellular Ca 2+as well as sarcoplasmic reticulum store Ca 2+were significantly decreased in ASMCs from α2 sm+mice compared to WT mice. In summary, enhanced Ca 2+clearance and depressed intracellular Ca 2+that occurs with increased NKA may underlie the observed hypotension in α2 sm+mice. Importantly, our data provide evidence that NKA may involve a larger Ca 2+clearance unit including at least NCX, SERCA, and PMCA.
Dr. Richard Paul (Advisor)
179 p.
transgenic mice; hypertension; vascular smooth muscle; Na+-Ca2+ exchanger

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Citations

  • PRITCHARD, T. J. (2007). Expression and Function of the Na +-K +ATPase α-Isoforms in Smooth Muscle: Evidence from Transgenic Mice [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1186672962

    APA Style (7th edition)

  • PRITCHARD, TRACY. Expression and Function of the Na +-K +ATPase α-Isoforms in Smooth Muscle: Evidence from Transgenic Mice. 2007. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1186672962.

    MLA Style (8th edition)

  • PRITCHARD, TRACY. "Expression and Function of the Na +-K +ATPase α-Isoforms in Smooth Muscle: Evidence from Transgenic Mice." Doctoral dissertation, University of Cincinnati, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1186672962

    Chicago Manual of Style (17th edition)

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This open access ETD is published by University of Cincinnati and OhioLINK.