GeroScienceSep 10, 2026

A type of HDL with high apolipoprotein(a) speeds up blood vessel aging and artery disease by causing blood vessel lining cells to age

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Sep 11, 2026

Abstract

Plasma H5 levels were significantly elevated in individuals with cardiovascular disease risk (4.0 ± 3.5% vs. 2.7 ± 1.0%, p = 0.024).

H5 is a highly electronegative HDL subfraction characterized by impaired cholesterol efflux.
Elevated H5 levels are independently associated with increased intima-media thickness and plaque burden in individuals with cardiovascular disease risk.
The lipoproteome of H5 is distinct and enriched with apolipoproteins such as Apo(a), ApoB, and ApoC3.
H5 induces endothelial dysfunction through mechanisms involving reactive oxygen species accumulation, DNA damage, and cellular aging.
The p53-p21 signaling pathway mediates H5-induced endothelial dysfunction in both in vitro and in vivo models.
In mice, H5 promotes a pro-atherogenic phenotype, suggesting a potential link to atherosclerotic cardiovascular disease risk.

Simplified

The limited benefits of high-density lipoprotein (HDL)-targeted therapies have shifted the research focus to HDL quality; some HDL subtypes may be pro-atherogenic and may counteract the potential benefits of HDL therapies. This study investigated the pathological mechanism of H5, a highly electronegative and compositionally abnormal HDL subfraction characterized by impaired cholesterol efflux. We used anion-exchange chromatography to separate HDL into five subfractions (H1-H5) from blood from 131 asymptomatic individuals (95 with metabolic syndrome and 36 without [controls]). Plasma H5 levels were significantly elevated in individuals with cardiovascular disease risk compared to controls (4.0 ± 3.5% vs. 2.7 ± 1.0%, p = 0.024). Clinically, elevated H5 levels were independently associated with structural markers of subclinical carotid atherosclerosis, including increased intima-media thickness (IMT) and plaque burden, in an imaging cohort of 118 participants. Mechanistically, the triglyceride-rich H5 showed a distinct lipoproteome, enriched with apolipoproteins including Apo(a), ApoB, and ApoC3. H5 induced endothelial dysfunction through pathways associated with reactive oxygen species (ROS) accumulation, DNA damage, and cellular senescence in vitro and in vivo. The p53-p21 signaling axis was the central mediator of this H5-induced dysfunction. In mice, H5-induced dysfunction promoted a pro-atherogenic phenotype, mediated centrally by the p53-p21 signaling axis. Our study suggests that elevated Apo(a)-rich H5 levels are associated with atherosclerotic cardiovascular disease (ASCVD) risk and validates targeting HDL quality-specifically the H5 subfraction-as a novel therapeutic strategy.

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A type of HDL with high apolipoprotein(a) speeds up blood vessel aging and artery disease by causing blood vessel lining cells to age

Abstract

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