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University of Cincinnati

1. PRITCHARD, TRACY J. Expression and Function of the Na +-K +ATPase a-Isoforms in Smooth Muscle: Evidence from Transgenic Mice.

Degree: PhD, Medicine : Molecular and Cellular Physiology, 2007, University of Cincinnati

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 a1- or a2-isoform (a1 sm+or a2 sm+mice) ligated to the smooth muscle specific a-actin promoter, SMP8. The a1 sm+mice displayed a 1.5-fold increase in the a1-isoform, while the a2 sm+mice had a 2-6-fold increase in the a2-isoform. Interestingly, the a-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 a-isoform protein was accompanied by a ~1.25- to 2.5-fold increase in NKA activity in gastric antrum from a1 sm+and a2 sm+mice respectively. The a2 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 a1 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 a-isoforms. Additionally, increasing smooth muscle NKA decreases blood pressure, which appears to be dependent on the degree of a-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 a2 sm+aorta but not a1 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 a2 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 a2 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 a2 sm+mice. Importantly, our data provide evidence that NKA may involve a larger Ca 2+clearance unit including at least NCX, SERCA, and PMCA. Advisors/Committee Members: Paul, Dr. Richard (Advisor).

Subjects/Keywords: transgenic mice; hypertension; vascular smooth muscle; Na+-Ca2+ exchanger

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APA (6th Edition):

PRITCHARD, T. J. (2007). Expression and Function of the Na +-K +ATPase a-Isoforms in Smooth Muscle: Evidence from Transgenic Mice. (Doctoral Dissertation). University of Cincinnati. Retrieved from http://rave.ohiolink.edu/etdc/view?acc_num=ucin1186672962

Chicago Manual of Style (16th Edition):

PRITCHARD, TRACY J. “Expression and Function of the Na +-K +ATPase a-Isoforms in Smooth Muscle: Evidence from Transgenic Mice.” 2007. Doctoral Dissertation, University of Cincinnati. Accessed October 15, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1186672962.

MLA Handbook (7th Edition):

PRITCHARD, TRACY J. “Expression and Function of the Na +-K +ATPase a-Isoforms in Smooth Muscle: Evidence from Transgenic Mice.” 2007. Web. 15 Oct 2019.

Vancouver:

PRITCHARD TJ. Expression and Function of the Na +-K +ATPase a-Isoforms in Smooth Muscle: Evidence from Transgenic Mice. [Internet] [Doctoral dissertation]. University of Cincinnati; 2007. [cited 2019 Oct 15]. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1186672962.

Council of Science Editors:

PRITCHARD TJ. Expression and Function of the Na +-K +ATPase a-Isoforms in Smooth Muscle: Evidence from Transgenic Mice. [Doctoral Dissertation]. University of Cincinnati; 2007. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1186672962

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