Human Genotyping and An Experimental Model Reveal NPR-C as A Possible Contributor to Morbidity In Coarctation Of The Aorta

Authors

John F. LaDisa Jr., Marquette UniversityFollow
Aoy Tomita-Mitchell, Medical College of Wisconsin
Karl D. Stamm, Medical College of WisconsinFollow
Kathleen Bazan, Medical College of WisconsinFollow
Donna K. Mahnke, Medical College of Wisconsin
Mary A. Goetsch, Medical College of Wisconsin
Brandon Wegter, Marquette University
Jesse W. Gerringer, Marquette University
Kathryn Repp, Marquette University
Oleg Palygin, Medical College of Wisconsin
Adrian P. Zietara, Medical College of Wisconsin
Mary M. Krolikowski, Medical College of WisconsinFollow
Thomas J. Eddinger, Marquette UniversityFollow
Abdel A. Alli, University of Florida College of Medicine
Michael E. Mitchell, Medical College of WisconsinFollow

Document Type

Article

Language

eng

Publication Date

6-2019

Publisher

American Physiological Society

Source Publication

Physiological Genomics

Source ISSN

1094-8341

Abstract

Coarctation of the aorta (CoA) is a common congenital cardiovascular (CV) defect characterized by a stenosis of the descending thoracic aorta. Treatment exists, but many patients develop hypertension (HTN). Identifying the cause of HTN is challenging because of patient variability (e.g., age, follow-up duration, severity) and concurrent CV abnormalities. Our objective was to conduct RNA sequencing of aortic tissue from humans with CoA to identify a candidate gene for mechanistic studies of arterial dysfunction in a rabbit model of CoA devoid of the variability seen with humans. We present the first known evidence of natriuretic peptide receptor C (NPR-C; aka NPR3) downregulation in human aortic sections subjected to high blood pressure (BP) from CoA versus normal BP regions (validated to PCR). These changes in NPR-C, a gene associated with BP and proliferation, were replicated in the rabbit model of CoA. Artery segments from this model were used with human aortic endothelial cells to reveal the functional relevance of altered NPR-C activity. Results showed decreased intracellular calcium ([Ca²⁺]_i) activity to C-type natriuretic peptide (CNP). Normal relaxation induced by CNP and atrial natriuretic peptide was impaired for aortic segments exposed to elevated BP from CoA. Inhibition of NPR-C (M372049) also impaired aortic relaxation and [Ca²⁺]_i activity. Genotyping of NPR-Cvariants predicted to be damaging revealed that rs146301345 was enriched in our CoA patients, but sample size limited association with HTN. These results may ultimately be used to tailor treatment for CoA based on mechanical stimuli, genotyping, and/or changes in arterial function.

Comments

Accepted version. Physiological Genomics, Vol. 51, No. 6 (June 2019) : 177-185. DOI. © 2019 American Physiological Society. Used with permission.

Recommended Citation

LaDisa, John F. Jr.; Tomita-Mitchell, Aoy; Stamm, Karl D.; Bazan, Kathleen; Mahnke, Donna K.; Goetsch, Mary A.; Wegter, Brandon; Gerringer, Jesse W.; Repp, Kathryn; Palygin, Oleg; Zietara, Adrian P.; Krolikowski, Mary M.; Eddinger, Thomas J.; Alli, Abdel A.; and Mitchell, Michael E., "Human Genotyping and An Experimental Model Reveal NPR-C as A Possible Contributor to Morbidity In Coarctation Of The Aorta" (2019). Biological Sciences Faculty Research and Publications. 774.
https://epublications.marquette.edu/bio_fac/774