Human genotyping and an experimental model reveal NPR-C as a possible contributor to morbidity in coarctation of the aorta

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.

C Type Natriuretic Peptide Receptor Activation Inhibits Sodium Channel Activity in Human Aortic Endothelial Cells by Activating the Diacylglycerol-Protein Kinase C Pathway

“…In this study we investigated the regulation of EnNaC expression and activity after NPRC ligand binding in hAoECs. We previously showed EnNaC [29] and NPRC [30] proteins are both expressed in these cells, but this is the first investigation of a cross-talk between EnNaC and NPRC. In addition, we showed an elevation of various DAGs in hAoECs after activation of NPRC by the agonist cANF.…”

A workflow for viewing biomedical computational fluid dynamics results and corresponding data within virtual and augmented reality environments

“…The thoracic aorta simulation featured here leverages data, methods and results discussed in detail elsewhere (25,26,27,28). Briefly, the simulation focuses on coarctation of the aorta (CoA), one of the most common congenital cardiovascular defects (29).…”

Molecular mechanisms for the prevention and promoting the recovery from ischemic stroke by nutraceutical laminarin: A comparative transcriptomic approach

“…Another genome-wide association study on human primary vascular smooth muscle cells and endothelial cells from different individuals identified that genetic variants at the NPR3 locus are associated with elevated blood pressure (27). NPR3 was found to be downregulated in human aortic sections subjected to high blood pressure from coarctation of the aorta (28), suggesting that NPR3 could be a therapeutic target for vascular disease prevention. In addition to NPR3, BDKRB2 has also been found to be involved in endothelial function and blood vessel constriction (29,30), thus determining cardiovascular health and regenerative arteriogenesis.…”