Association Between Plasma Fibulin-1 and Brachial-Ankle Pulse Wave Velocity in Arterial Stiffness

Abstract

Arterial stiffness forms the basis of cardiovascular diseases (CVD) and is also an independent predictor of CVD risk. Early detection and intervention of arterial stiffness are important for improving the global burden of CVD. Pulse wave velocity (PWV) is the gold standard for assessing arterial stiffness and the molecular mechanism of arterial stiffness remains to be studied. Extracellular matrix (ECM) remodeling is one of the major mechanisms of arterial stiffness. Partial quantitative changes of ECM proteins can be detected in plasma. Therefore, we examined the hypothesis that a discovery proteomic comparison of plasma proteins between high arterial stiffness (baPWV ≥ 1,400 cm/s) and normal arterial stiffness (baPWV < 1,400 cm/s) populations might identify relevant changed ECM proteins for arterial stiffness. Plasma samples were randomly selected from normal arterial stiffness (n = 6) and high arterial stiffness (n = 6) people. Isobaric tags for relative and absolute quantitation (iTRAQ) based quantitative proteomics technique was performed to find a total of 169 differentially expressed proteins (DEPs). Nine ECM proteins were included in all DEPs and were all up-regulated proteins. Fibulin-1 had the highest statistically fold-change (FC = 3.7, p < 0.0001) in the high arterial stiffness population compared with the control group during the nine ECM proteins. The expression of plasma fibulin-1 in normal arterial stiffness (n = 112) and high arterial stiffness (n = 72) populations was confirmed through enzyme-linked immunosorbent assay (ELISA). Similarly, ELISA results showed that plasma concentrations of fibulin-1 in the high arterial stiffness group were higher than those in the normal arterial stiffness group (12.69 ± 0.89 vs. 9.84 ± 0.71 μg/ml, p < 0.05). Univariate analysis of fibulin-1 with brachial-ankle pulse wave velocity (baPWV) indicated that fibulin-1 was positively correlated with baPWV in all participants (r = 0.32, p < 0.01) and a stronger positive correlation between baPWV and fibulin-1 in high arterial stiffness group (r = 0.64, p < 0.0001) was found. Multiple regression analysis of factors affecting baPWV showed that fibulin-1 was also a significant determinant of the increased ba-PWV (R2 = 0.635, p = 0.001). Partial correlation analysis showed that baPWV increased with the growth of plasma fibulin-1(r = 0.267, p < 0.001). In conclusion, our results demonstrated that fibulin-1 is positively correlated with ba-PWV and an independent risk factor for arterial stiffness.

Biomarkers of aging

“…Wu et al demonstrated that METTL3 was reduced in prematurely senescent hMPCs, and knockout of METTL3 also accelerated hMPC senescence, resulting from markedly reduced m 6 A modifications and destabilized MIS12 mRNA, a key regulator of cell proliferation (Wu et al, 2020c;Wu et al, 2022b). Another study showed that knockdown of METTL3 led to accelerated senescence by upregulating the expression of polo-like kinase 1 (PLK1), a critical cell cycle modulator, in an m 6 A-dependent manner (Luo et al, 2021). Moreover, knockout of obesity-associated protein (FTO), one of the "erasers" of m 6 A, also accelerated hMPC senescence, and downregulation of FTO led to increased overall m 6 A levels during ovarian aging in mice (Jiang et al, 2021;Sun et al, 2021;Zhang et al, 2022c).…”

“…The circulating fibroblast growth factor 21 (cFGF21) concentration is positively correlated with age (Yang et al, 2022a), and high levels of cFGF21 are closely associated with an increased risk of CVDs (Zhang et al, 2021h). Circulating fibulin-1 is positively correlated with brachial-ankle PWV and is an independent risk factor for arterial stiffness (Luo et al, 2022a). Other circulating factors, including oxidative stress and miRNAs, have also been reported as potential biomarkers of vascular aging (Du et al, 2021;Gopcevic et al, 2021).…”

Metabolic clues to aging: exploring the role of circulating metabolites in frailty, sarcopenia and vascular aging related traits and diseases

“…Notably, certain biomarkers independently associated with arterial stiffness include inflammatory biomarkers like C-reactive protein (CRP), IL-6, Klotho levels, and aldosterone ( Angoff et al, 2021 ). Our recent findings also demonstrate a positive correlation between circulating Fibulin-1 and brachial-ankle PWV, marking it as an independent risk factor for arterial stiffness ( Luo et al, 2022 ). In our study, we identified 19 metabolites with potential links to arterial stiffness, as suggested by MR estimates of IVW, but these require further clinical validation to confirm their role as biomarkers for arterial stiffness and vascular aging.…”

Spatiotemporal EP4-fibulin-1 expression is associated with vascular intimal hyperplasia

“…The levels of circulating fibulin-1 are positively correlated with arterial stiffness. 41, 42 Fibulin-1 is indicated to regulate tissue remodeling via promotion of cell migration in the heart and ductus arteriosus 13, 26 There are four splice variants of fibulin-1 in humans. Variants C and D are expressed to the same extent in most tissues and cell lines, whereas variants A and B are only detected at low levels in human placenta.…”