Key result
NOR-1 overexpression negatively modulated osteogenic gene expression and significantly reduced both in vitro and in vivo ectopic cardiovascular calcification.
Why the study?
Cardiovascular calcification pathophysiology is not fully understood, and the contribution of NOR-1 to ectopic calcification is unknown.
Does NOR-1 overexpression prevent osteogenic differentiation and ectopic cardiovascular calcification in vitro and in vivo?
Does NOR-1 overexpression prevent osteogenic differentiation and ectopic cardiovascular calcification in vitro and in vivo?
This basic science study identifies the nuclear receptor NOR-1 as a critical negative regulator of osteogenic transdifferentiation, offering a potential molecular target to mitigate ectopic cardiovascular calcification.
Hypothesis-generating for NOR-1 as an anti-calcification target; leaves open translation to human cardiovascular disease.
Cardiovascular calcification is a significant public health issue whose pathophysiology is not fully understood. NOR-1 regulates critical processes in cardiovascular remodeling, but its contribution to ectopic calcification is unknown. NOR-1 was overexpressed in human calcific aortic valves and calcified atherosclerotic lesions colocalizing with RUNX2, a factor essential for osteochondrogenic differentiation and calcification. NOR-1 and osteogenic markers were upregulated in calcifying human valvular interstitial cells (VICs) and human vascular smooth muscle cells (VSMCs). Gain- and loss-of-function approaches demonstrated that NOR-1 negatively modulates the expression of osteogenic genes relevant for the osteogenic transdifferentiation (RUNX2, IL-6, BMP2 and ALPL) and calcification of VICs. VSMCs from transgenic mice overexpressing NOR-1 in these cells (TgNOR-1VSMC) expressed lower basal levels of osteogenic genes (IL-6, BMP2, ALPL, OPN) than cells from WT littermates, and their upregulation by a high-phosphate osteogenic medium (OM) was completely prevented by NOR-1 transgenesis. Consistently, this was associated with a dramatic reduction in the calcification of both transgenic VSMCs and aortic rings from TgNOR-1VSMC mice exposed to OM. Atherosclerosis and calcification were induce in mice by the administration of AAV-PCSK9D374Y and a high-fat/high-cholesterol diet. Challenged-TgNOR-1VSMC mice exhibited decreased vascular expression of osteogenic markers, and both less atherosclerotic burden (assessed in whole aorta and lesion size in aortic arch and brachiocephalic artery) and less vascular calcification (assessed either by near-infrared fluorescence imaging or histological analysis) than WT mice. Our data indicate that NOR-1 negatively modulates the expression of genes critically involved in the osteogenic differentiation of VICs and VSMCs, thereby restraining ectopic cardiovascular calcification.
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Ballester‐Servera et al. (2023) studied Cardiovascular calcification and atherosclerosis. NOR-1 overexpression vs. Wild-type mice or control vector-transduced cells was evaluated on Vascular calcification and expression of osteogenic markers. NOR-1 overexpression negatively modulated osteogenic gene expression and significantly reduced both in vitro and in vivo ectopic cardiovascular calcification.
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