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. 2021 May 1;11(5):414.
doi: 10.3390/life11050414.

Association of SDF1 and MMP12 with Atherosclerosis and Inflammation: Clinical and Experimental Study

María Marcos-Jubilar  1 , Josune Orbe  2   3 , Carmen Roncal  2   3 , Florencio J D Machado  2 , José Antonio Rodriguez  2   3 , Alejandro Fernández-Montero  4 , Inmaculada Colina  5 , Raquel Rodil  6 , Juan C Pastrana  5 , José A Páramo  1   2   3
Affiliations

Association of SDF1 and MMP12 with Atherosclerosis and Inflammation: Clinical and Experimental Study

María Marcos-Jubilar et al. Life (Basel). .

Abstract

Background: Atherosclerosis is the main etiology of cardiovascular diseases (CVD), associated to systemic inflammation. Matrix metalloproteinases (MMPs) are related to atherosclerosis progression through the SDF1/CXCR4 axis promoting macrophages recruitment within the vascular wall. The goal was to assess new circulatory inflammatory markers in relation to atherosclerosis.

Methods: Measurement of SDF1, MMP12 and CRP in blood samples of 298 prospective patients with cardiovascular risk. To explore atherosclerosis progression, CXCR4/SDF1 axis and MMP12 expression were determined by RT-qPCR and by immunohistochemistry in the aorta of accelerated and delayed atherosclerosis mice models (Apoe-/- and Apoe-/-Mmp10-/-).

Results: SDF1, MMP12 and CRP were elevated in patients with clinical atherosclerosis, but after controlling by confounding factors, only SDF1 and CRP remained increased. Having high levels of both biomarkers showed 2.8-fold increased risk of presenting clinical atherosclerosis (p = 0.022). Patients with elevated SDF1, MMP12 and CRP showed increased risk of death in follow-up (HR = 3.2, 95%CI: 1.5-7.0, p = 0.004). Gene and protein expression of CXCR4 and MMP12 were increased in aortas from Apoe-/- mice.

Conclusions: The combination of high circulating SDF1, MMP12 and CRP identified patients with particular inflammatory cardiovascular risk and increased mortality. SDF1/CXCR4 axis and MMP12 involvement in atherosclerosis development suggests that they could be possible atherosclerotic targets.

Keywords: MMP-12; SDF1/CXCR4; atherosclerosis; cardiovascular risk; inflammation; multimarker approach.

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Conflict of interest statement

The authors declare no conflict of interest. The sponsors had no role in the design, execution, interpretation, or writing of the study.

Figures

Figure 1
Figure 1
Survival according to combined risk variable. Combine risk variable stablished by the combination of SDF1, MMP12 and CRP. High risk: 3rd tercile SDF1 & MMP12 & CRP (n = 27), low risk: 1st tercile SDF1 & MMP12 & CRP (n = 15) and medium risk: any other combination (n = 256). Kaplan-Meier survival plots are unadjusted for covariates. A log-rank test of survival across risk levels of the combined variable is highly significant (p < 0.001).
Figure 2
Figure 2
SDF1, CXCR4 and MMP12 expression in murine atherosclerotic aortas. (a) mRNA levels of SDF1 in aortas of Apoe-/- and Apoe-/-Mmp10-/- (2KO) mice at 10 and 16 months of age (n = 5/time point). (b) Aortic expression of CXCR4 was decreased in 2KO mice (n = 5/time point) vs. Apoe-/- at 16 months. (c) 2KO presented a reduction of MMP12 (n = 5/time point) vs. Apoe-/- at 10 months. * p < 0.05.
Figure 3
Figure 3
CXCR4 and MMP12 expression in murine atherosclerotic aortas. Expression of MMP12 in Apoe-/- mice (A) and 2KO mice (B) at 6 months. Expression of MMP12 in Apoe-/- mice (C) and 2KO mice (D) at 12 months. (E) Box plot showing the quantification of MMP12 expression in atherosclerotic plaques. Expression of CXCR4 in Apoe-/- mice (F) and 2KO mice (G) at 6 months. Expression of CXCR4 in Apoe-/- mice (H) and 2KO mice (I) at 12 months. (J) Box plot showing the quantification of CXCR4 expression in atherosclerotic plaques.
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