Faculty Collaboration Database

Human genotyping and an experimental model reveal NPR-C as a possible contributor to morbidity in coarctation of the aorta. Physiol Genomics 2019 Jun 01;51(6):177-185

Date

04/20/2019

Pubmed ID

31002586

Pubmed Central ID

PMC6620646

DOI

10.1152/physiolgenomics.00049.2018

Scopus ID

2-s2.0-85066457176 (requires institutional sign-in at Scopus site)   15 Citations

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-C variants 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.

Author List

LaDisa JF Jr, Tomita-Mitchell A, Stamm K, Bazan K, Mahnke DK, Goetsch MA, Wegter BJ, Gerringer JW, Repp K, Palygin O, Zietara AP, Krolikowski MM, Eddinger TJ, Alli AA, Mitchell ME

Authors

Jesse W. Gerringer Postdoctoral Researcher 1 in the Biomedical Engineering department at Medical College of Wisconsin
John F. LaDisa PhD Professor in the Pediatrics department at Medical College of Wisconsin
Donna K. Mahnke Research Scientist I in the Pediatrics department at Medical College of Wisconsin
Michael Edward Mitchell MD Chief, Professor in the Surgery department at Medical College of Wisconsin
Aoy Tomita Mitchell PhD Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Aorta
Aortic Coarctation
Blood Pressure
Calcium
Child
Child, Preschool
Down-Regulation
Endothelial Cells
Female
Genotype
Humans
Infant
Male
Models, Theoretical
Muscle, Smooth, Vascular
Natriuretic Peptide, C-Type
Oligopeptides
Quinoxalines
Rabbits
Vasodilation