Dataset Information

PTH-induced EndMT via miR-29a-5p/GSAP/Notch1 pathway contributed to valvular calcification in rats with CKD.

ABSTRACT:

Background

Endothelial-to-mesenchymal transition (EndMT) is a common pathophysiology in valvular calcification (VC) among non-chronic kidney disease (CKD) patients. However, few studies were investigated in CKD-induced VC. Parathyroid hormone (PTH) was considered to be an important component of EndMT in CKD-induced cardiovascular diseases. Therefore, determining whether PTH could induce valvular EndMT and elucidating corresponding mechanism involved further study.

Methods

Performing a 5/6 nephrectomy with a high phosphorus diet was done to construct VC models in rats with CKD. miRNA sequencing was used to ascertain changes in microRNA in human umbilical vein endothelial cells (HUVECs) intervened by PTH. VC was observed by Von Kossa staining and scanning electron microscope.

Results

PTH induced valvular EndMT in VC. Global microRNA expression profiling of HUVECs was examined in PTH versus the control in vitro, in which miR-29a-5p was most notably decreased and was resumed by PTHrP(7-34) (PTH-receptor1 inhibitor). Overexpression of miR-29a-5p could inhibit PTH-induced EndMT in vitro and valvular EndMT in vivo. The dual-luciferase assay verified that γ-secretase-activating protein (GASP) served as the target of miR-29a-5p. miR-29a-5p-mimics, si-GSAP and DAPT (γ-secretase inhibitor) inhibited PTH-induced γ-secretase activation, thus blocking Notch1 pathway activation to inhibit EndMT in vitro. Moreover, Notch1 pathway activation was observed in VC. Blocking Notch1 pathway activation via AAV-miR-29a and DAPT inhibited valvular EndMT. In addition, blocking Notch1 pathway activation was also shown to alleviate VC.

Conclusion

PTH activates valvular EndMT via miR-29a-5p/GSAP/Notch1 pathway, which can contribute to VC in CKD rats.

SUBMITTER: Wang L

PROVIDER: S-EPMC8168417 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease. METHODS:We determined genomewide associations with the presence of aortic-valve calcification (among 6942 participants) and mitral annular calcification (among 3795 participants), as detected by computed tomographic (CT) scanning; the study population for this analysis included persons of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population). Findings were replicated in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis. RESULTS:One SNP in the lipoprotein(a) (LPA) locus (rs10455872) reached genomewide significance for the presence of aortic-valve calcification (odds ratio per allele, 2.05; P=9.0×10(-10)), a finding that was replicated in additional white European, African-American, and Hispanic-American cohorts (P<0.05 for all comparisons). Genetically determined Lp(a) levels, as predicted by LPA genotype, were also associated with aortic-valve calcification, supporting a causal role for Lp(a). In prospective analyses, LPA genotype was associated with incident aortic stenosis (hazard ratio per allele, 1.68; 95% confidence interval [CI], 1.32 to 2.15) and aortic-valve replacement (hazard ratio, 1.54; 95% CI, 1.05 to 2.27) in a large Swedish cohort; the association with incident aortic stenosis was also replicated in an independent Danish cohort. Two SNPs (rs17659543 and rs13415097) near the proinflammatory gene IL1F9 achieved genomewide significance for mitral annular calcification (P=1.5×10(-8) and P=1.8×10(-8), respectively), but the findings were not replicated consistently. CONCLUSIONS:Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aortic-valve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.).