Abstract
Atherosclerotic cardiovascular disease (ACVD) is a lipid-driven inflammatory disease and one of the leading causes of death worldwide. Lipid deposits in the arterial wall lead to the formation of plaques that involve lipid oxidation, cellular necrosis, and complement activation, resulting in inflammation and thrombosis. The present study found that homozygous deletion of the CFHR1 gene, which encodes the plasma complement protein factor H-related protein 1 (FHR-1), was protective in two cohorts of patients with ACVD, suggesting that FHR-1 accelerates inflammation and exacerbates the disease. To test this hypothesis, FHR-1 was isolated from human plasma and was found to circulate on extracellular vesicles and to be deposited in atherosclerotic plaques. Surface-bound FHR-1 induced the expression of pro-inflammatory cytokines and tissue factor in both monocytes and neutrophils. Notably, plasma concentrations of FHR-1, but not of factor H, were significantly (p < 0.001) elevated in patients with ACVD, and correlated with the expression of the inflammation markers C-reactive protein, apolipoprotein serum amyloid protein A, and neopterin. FHR-1 expression also significantly correlated with plasma concentrations of low-density lipoprotein (LDL) (p < 0.0001) but not high-density lipoprotein (HDL). Taken together, these findings suggest that FHR-1 is associated with ACVD.
Highlights
Inflammation is a hallmark of many diseases and represents an innate immune response to tissue injury and infection, as well as metabolic stress
Factor H-related protein 1 (FHR-1) binding to necrotic cells was previously observed in damaged kidney tissues of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), with serum concentrations of FHR-1 correlating with disease progression[13]
We hypothesized that the protective effect of ∆CFHR3/1 could be explained by the previously described pro-inflammatory activity of FHR-113 and assessed whether ∆CFHR3/1 protects against Atherosclerotic cardiovascular disease (ACVD)
Summary
Inflammation is a hallmark of many diseases and represents an innate immune response to tissue injury and infection, as well as metabolic stress. Inflammation is usually followed by clearance and healing processes, sustained immune responses that accompany permanent inflammation can cause serious inflammatory injury in the host These findings have been observed in patients with atherosclerotic cardiovascular disease (ACVD), a condition that has a substantial negative effect on public health[1]. Because patients with ACVD often have hyperlipidemia, permanent inflammation, and plaques containing oxLDL and necrotic cells, the present study investigated the functions of FHR-1 in greater detail by evaluating its activity in patients with ACVD. It remains unclear, whether FHR-1 binds to acellular necrotic cores in plaques of ACVD patients, thereby contributing to plaque vulnerability
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