Natriuretic Peptide Receptor 2 Locus Contributes to Carotid Remodeling

Abstract

Background Carotid artery intima/media thickness ( IMT ) is a hallmark trait associated with future cardiovascular events. The goal of this study was to map new genes that regulate carotid IMT by genome‐wide association. Methods and Results We induced IMT by ligation procedure of the left carotid artery in 30 inbred mouse strains. Histologic reconstruction revealed significant variation in left carotid artery intima, media, adventitia, external elastic lamina volumes, intima‐to‐media ratio, and (intima+media)/ external elastic lamina percent ratio in inbred mice. The carotid remodeling trait was regulated by distinct genomic signatures with a dozen common single‐nucleotide polymorphisms associated with left carotid artery intima volume, intima‐to‐media ratio, and (intima+media)/ external elastic lamina percent ratio. Among genetic loci on mouse chromosomes 1, 4, and 12, there was natriuretic peptide receptor 2 ( Npr2 ), a strong candidate gene. We observed that only male, not female, mice heterozygous for a targeted Npr2 deletion ( Npr2 +/− ) exhibited defective carotid artery remodeling compared with Npr2 wild‐type ( Npr2 +/+ ) littermates. Fibrosis in carotid IMT was significantly increased in Npr2 +/− males compared with Npr2 +/− females or Npr2 +/+ mice. We also detected decreased Npr2 expression in human atherosclerotic plaques, similar to that seen in studies in Npr2 +/− mice. Conclusions We found that components of carotid IMT were regulated by distinct genetic factors. We also showed a critical role for Npr2 in genetic regulation of vascular fibrosis associated with defective carotid remodeling.

The Predictive Value of A, B, and C-Type Natriuretic Peptides in People at Risk of Heart Disease: Protocol for a Longitudinal Observational Study

“…In this context, it is relevant to note that an increase in plasma NTproCNP was independently linked to adverse outcome in patients with HFpEF [ 71 ]. Aligning with CNP’s adaptive role in combatting arteriosclerosis [ 21 , 22 ], we also anticipate carotid artery intimal thickening will correlate with CNP values at 50 years of age and with the proportional increase of CNP above values at baseline.…”

“…However, in both community studies [ 15 , 16 ], we found plasma CNP products—opposite to ANP and BNP—are higher in those with impaired cardiometabolic health. We suggest that these associations with CNP likely reflect an adaptive compensatory response to inflammation in vascular [ 21 , 22 ] and myocardial tissues [ 2 , 23 , 24 ]. Notably, in both age groups, plasma CNP was positively associated with markers of arterial and left ventricular stiffness in both sexes, whereas these associations with BNP were inverse except in older women ( Figure 2 ).…”

Association of natriuretic peptides and receptor activity with cardio-metabolic health at middle age

“…On the other hand, the emergence of CNP’s impact on a quite different receptor (NPR2) comes to light presumably via multiple small contributions to circulating cGMP across a range of tissues, including CNP gene upregulation in the renal glomerulus, and secretions from the myocardial tissues as evidenced by associations of CNP with cardiac function ( Supplementary Table S2 ). Although CNP has important actions in maintaining vascular integrity 33 , 34 and in regulating blood pressure and flow in the microcirculation 35 , the largely sub endothelial location of NPR2, and the low abundance of bioactive CNP, likely account for the negligible impact of CNP on cGMP—relative to actions of ANP in the more accessible vascular endothelial tissues. Substituting bio-inactive NP forms for bio-active NPs did not alter the findings from modelling except CNP was no longer a significant predictor of cGMP in the complete model ( Supplementary Table S3 ), and the inhibitory impact of BMI and eGFR were lost.…”